Vimovo^® (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca UK Limited (United Kingdom)

Manufactured By

Patheon Pharmaceuticals, Inc. (USA)

ATC Code

M01AE52 (Naproxen and Esomeprazole)

Active Substances

Naproxen (Rec.INN registered by WHO)

Esomeprazole (Rec.INN registered by WHO)

Dosage Form

Vimovo®

Enteric-coated tablets, 500 mg+20 mg: 6 or 60 pcs.

Dosage Form, Packaging, and Composition

Enteric-coated tablets (film-coated) yellow, oval, with the inscription “500/20” on one side, printed in black dye.

Excipients : croscarmellose sodium – 22 mg, povidone K90 – 11 mg, colloidal silicon dioxide – 2.62 mg, magnesium stearate – 1.38 mg, hypromellose 3 mPa·s – 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, methylparahydroxybenzoate (E218) – about 20 µg, propylparahydroxybenzoate (E216) – about 10 µg, methacrylic acid and ethyl acrylate copolymer (1:1), 30% suspension – 54.6 mg, titanium dioxide – 13.26 mg, polydextrose (E1200) – 6.3 mg, hypromellose 6 mPa·s – 10.85 mg, hypromellose 50 mPa·s – 680 µg, yellow iron oxide (E172) – 580 µg, carnauba wax – 50 µg, black ink (opacode black) – q.s.

Composition of black ink (opacode black) black iron oxide – 22%, hypromellose 6 mPa·s – 7%, propylene glycol – 10%, isopropanol (removed during manufacturing) – 12%, purified water (removed during manufacturing) – 49%.

6 pcs. – plastic bottles (1) – cardboard packs.
60 pcs. – plastic bottles (1) – cardboard packs.

Clinical-Pharmacological Group

NSAID in combination with a proton pump inhibitor

Pharmacotherapeutic Group

NSAID + Gastric iron secretion reducing agent – proton pump inhibitor

Pharmacological Action

A combined drug containing an NSAID and a proton pump inhibitor. Vimovo^® is developed as tablets with sequential drug delivery: the coating contains immediate-release esomeprazole magnesium, and the core contains delayed-release naproxen, coated with an enteric coating. As a result, esomeprazole is released in the stomach before naproxen dissolves in the small intestine. The enteric coating prevents the release of naproxen at pH below 5.5, providing protection from the potential negative effects of naproxen on the gastric mucosa.

Naproxen is an NSAID with analgesic and antipyretic effects. The mechanism of action of the naproxen anion, like other NSAIDs, is not fully understood but may be associated with the suppression of prostaglandin synthetase.

Esomeprazole is a proton pump inhibitor, the S-isomer of omeprazole, and reduces the secretion of hydrochloric acid in the stomach by specifically inhibiting the proton pump in the parietal cells of the stomach. The S- and R-isomers of omeprazole have similar pharmacodynamic activity.

Esomeprazole is a weak base that converts to the active form in the highly acidic environment of the secretory canaliculi of the gastric parietal cells and inhibits the proton pump – the enzyme H⁺/K⁺-ATPase, thereby inhibiting both basal and stimulated secretion of hydrochloric acid.

Effect on gastric acid secretion

After 9 days of twice-daily administration of three Vimovo^® combinations: Naproxen 500 mg combined with esomeprazole at doses of 10 mg, 20 mg, or 30 mg, gastric pH above 4 was maintained for an average of 9.8 h, 17.1 h, and 18.4 h, respectively, over 24 hours in healthy volunteers. The variability of individual values for the time of maintaining gastric pH above 4 , expressed as the coefficient of variability (CV), was 55%, 18%, and 16%, respectively.

Other effects related to inhibition of gastric acid secretion. During treatment with drugs that reduce gastric secretion, the concentration of gastrin in plasma increases as a result of reduced acid secretion.

Due to the decrease in hydrochloric acid secretion, the concentration of chromogranin A (CgA) increases. An increase in CgA concentration may affect the results of examinations for detecting neuroendocrine tumors. To prevent this influence, it is necessary to temporarily stop taking esomeprazole 5 days before conducting the CgA concentration test.

In patients receiving long-term esomeprazole therapy, an increase in the number of enterochromaffin-like cells is observed, probably associated with an increase in plasma gastrin concentration.

In patients taking drugs that reduce gastric secretion for a long time, the formation of glandular cysts in the stomach is more frequently observed. These phenomena are due to physiological changes resulting from pronounced inhibition of hydrochloric acid secretion. The cysts are benign and undergo reverse development.

The use of drugs that suppress the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of microbial flora normally present in the gastrointestinal tract in the stomach. The use of proton pump inhibitors may lead to a slight increase in the risk of infectious diseases of the gastrointestinal tract caused by bacteria of the genus Salmonella spp. and Campylobacter spp., and possibly also by Clostridium difficile bacteria in hospitalized patients.

Clinical efficacy and safety

Vimovo^® at a dose of 500 mg/20 mg twice daily significantly reduced the incidence of NSAID-associated ulcers in patients not infected with Helicobacter pylori, belonging to the risk group (elderly age, history of gastric or duodenal ulcer), compared with naproxen in enteric-coated tablets at 500 mg twice daily during 6-month therapy in combination with other proton pump inhibitors or in monotherapy. The incidence of gastric ulcer with Vimovo^® was 5.6, and with naproxen – 23.7. Taking Vimovo^® also reduced the incidence of duodenal ulcers compared with naproxen therapy (0.7% and 5.4%, respectively).

In patients receiving Vimovo^®, a lower frequency of NSAID-related upper gastrointestinal adverse effects was observed compared to patients taking Naproxen in enteric-coated tablets (53.3% and 70.4%, respectively).

In patients receiving Vimovo^® and low-dose acetylsalicylic acid, a lower incidence of gastric and duodenal ulcers was observed compared to 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%, while in patients receiving Naproxen in enteric-coated tablets it was 30.1%.

In patients receiving Vimovo^® for 6 months, a lower frequency of dyspepsia symptoms was noted compared to taking naproxen in enteric-coated tablets.

Patients receiving Vimovo^® discontinued therapy less frequently due to the development of adverse effects (7.9%) compared to patients receiving Naproxen in enteric-coated tablets (12.5%). The frequency of therapy discontinuation due to upper gastrointestinal adverse effects was also lower with Vimovo^® therapy (4% and 12%, respectively). The average duration of Vimovo^® therapy was 152 days compared to 124 days of naproxen monotherapy.

In osteoarthritis of the knee joint, similar efficacy of Vimovo^® at a dose of 500 mg/20 mg twice daily and celecoxib at a dose of 200 mg/day was observed when taken for 12 weeks of therapy. The frequency of therapy discontinuation due to adverse effects was also similar.

Pharmacokinetics

Absorption

Naproxen. At steady state after twice-daily administration of Vimovo^®, the C_max of naproxen in plasma is reached on average within 3 h after taking the drug in the morning and evening. The T_max of naproxen in plasma is slightly longer on the first day of therapy, with median times after morning and evening intake being 4 h and 5 h, respectively.

Bioequivalence of Vimovo^® and enteric-coated naproxen was proven based on the AUC and C_max values of naproxen in plasma.

Naproxen is rapidly and completely absorbed from the gastrointestinal tract, bioavailability is 95%. C_ss of naproxen is achieved after 4-5 days of administration.

Taking Vimovo^® with food does not affect the extent of naproxen absorption but significantly delays (by 8 h) absorption and reduces C_max in plasma by 12%. Taking Vimovo^® 30 minutes before meals did not affect (or only minimally) the extent and time of naproxen absorption compared to taking Vimovo^® with food.

Esomeprazole. After twice-daily administration of Vimovo^®, esomeprazole is rapidly absorbed, reaching C_max in plasma, on average, within 0.5-0.75 h after morning and evening intake on the first day and after reaching steady state.

C_max in plasma is higher at steady state compared to the concentration on the first day of Vimovo^® intake. This is partly explained by enhanced absorption due to the pharmacodynamic effect of esomeprazole, which increases gastric pH, leading to a reduction in the acid degradation of esomeprazole in the stomach. A reduction in presystemic metabolism and systemic clearance of esomeprazole upon repeated administration of the drug also contributes to the increase in plasma concentrations of esomeprazole at steady state.

Taking Vimovo^® with food does not delay the absorption of esomeprazole but significantly reduces the extent of absorption, leading to a 52% and 75% reduction in AUC and C_max in plasma, respectively. Taking Vimovo^® 30 minutes before meals did not significantly affect the rate and extent of esomeprazole absorption compared to taking Vimovo^® with food.

Distribution

Naproxen. The binding of naproxen at therapeutic concentrations to plasma albumin is more than 99%. The V_d of naproxen is 0.16 L/kg. When naproxen is taken in doses greater than 500 mg/day, plasma concentrations increase less than proportionally to the dose due to increased clearance resulting from saturable binding to plasma proteins at higher doses (mean minimum C_ss 36.5, 49.2, and 56.4 mg/L after taking naproxen at daily doses of 500, 1000, and 1500 mg, respectively). The naproxen anion was detected in breast milk in women at a concentration of approximately 1% of the C_max of naproxen in plasma.

Esomeprazole. The binding of esomeprazole to plasma proteins is 97%. The apparent V_d of esomeprazole at steady state in healthy volunteers is approximately 0.22 L/kg body weight.

Metabolism

Naproxen. Naproxen is extensively metabolized in the liver by cytochrome P450 system isoenzymes, mainly the CYP2C9 isoenzyme, to form 6-O-desmethylnaproxen. The unchanged drug or its metabolites do not induce these isoenzymes. Naproxen and 6-O-desmethylnaproxen are further metabolized to their respective acyl glucuronide conjugated metabolites. In accordance with the T_1/2 of naproxen, the AUC increases upon repeated administration of Vimovo^® twice daily.

Esomeprazole. Esomeprazole is completely metabolized by cytochrome P450 system isoenzymes. A significant portion of esomeprazole metabolism depends on the polymorphic enzyme CYP2C19, which is responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The remainder depends on another specific isoform, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in plasma. The main metabolites of esomeprazole do not affect gastric acid secretion.

The AUC of esomeprazole increases upon repeated administration of Vimovo^® twice daily. This increase is dose-dependent and explains the nonlinear relationship between dose and AUC after repeated administration of the drug. This time- and dose-dependence is partly due to a reduction in presystemic metabolism and systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and/or its sulfone metabolite. Increased absorption of esomeprazole upon repeated administration of Vimovo^® likely also contributes to the time and dose dependence.

Excretion

Naproxen. After twice-daily administration of Vimovo^®, the mean T_1/2 of naproxen is approximately 9 h and 15 h after morning and evening intake, respectively, and does not change upon repeated administration of the drug.

The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of naproxen from any dose is excreted in the urine, mainly as naproxen (<1%), 6-O-desmethylnaproxen (<1%), or their conjugates (from 66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. Metabolites may accumulate in patients with renal insufficiency.

Esomeprazole. After twice-daily administration of Vimovo^®, the mean T_1/2 of esomeprazole is approximately 1 h after morning and evening intake on the first day and slightly prolongs after reaching steady state (1.2-1.5 h).

The total plasma clearance of esomeprazole is 17 L/h after a single dose and 9 L/h after repeated administration.

Almost 80% of the esomeprazole dose after oral administration is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the unchanged drug is excreted in the urine.

Pharmacokinetics in special clinical situations

Patients with renal insufficiency. Pharmacokinetic studies of Vimovo^® have not been conducted in patients with renal insufficiency.

Naproxen pharmacokinetic parameters of naproxen have not been determined in patients with renal insufficiency. Since Naproxen, its metabolites and conjugates are mainly excreted in the urine, accumulation of naproxen metabolites is possible in case of renal insufficiency. In patients with severe renal insufficiency, the elimination of naproxen is reduced. It is not recommended to use Vimovo^® in patients with severe renal insufficiency (CrCl < 30 mL/min).

Esomeprazole studies of esomeprazole have not been conducted in patients with impaired renal function. Since the excretion of esomeprazole metabolites, not the parent drug, is carried out by the kidneys, no change in esomeprazole metabolism is expected in patients with impaired renal function.

Patients with hepatic insufficiency. Pharmacokinetic studies of Vimovo^® have not been conducted in patients with hepatic insufficiency.

Naproxen pharmacokinetic parameters of naproxen have not been determined in patients with hepatic insufficiency. Alcoholic cirrhosis and probably other forms of cirrhosis reduce the total plasma concentration of naproxen but increase the concentration of unbound naproxen in plasma. The applicability of these data to naproxen in the Vimovo^® preparation is unknown, but in such situations, it is advisable to prescribe the drug at the minimum effective dose.

Esomeprazole mild or moderate hepatic insufficiency may affect the metabolism of esomeprazole. The metabolic rate is reduced in patients with severe hepatic insufficiency, leading to a doubling of the AUC of esomeprazole. Therefore, the maximum daily dose of esomeprazole of 20 mg should not be exceeded in patients with severe hepatic insufficiency.

Vimovo^® should not be prescribed to patients with severe hepatic insufficiency.

Elderly patients. There are no pharmacokinetic data for Vimovo^® in patients over 65 years of age.

Naproxen studies show that although the total plasma concentration of naproxen does not change, the unbound fraction of naproxen in plasma increases in elderly patients; however, the unbound fraction is less than 1% of the total naproxen concentration. C_min of unbound naproxen in elderly patients ranged from 0.12% to 0.19% of the total naproxen concentration compared to 0.05%-0.075% in young patients. The clinical significance of these data is unknown, although it is possible that an increase in free naproxen concentration may be accompanied by an increased frequency of adverse events at a given dose in some elderly patients.

Esomeprazole the metabolism of esomeprazole does not change significantly in elderly patients aged 71 to 80 years.

Pharmacokinetic features in certain patient groups. Approximately 2.9±1.5% of the population has reduced activity of the CYP2C19 isoenzyme. In such patients, the metabolism of esomeprazole occurs mainly as a result of the action of CYP3A4. With systematic administration of esomeprazole at a dose of 40 mg once daily, the mean AUC is 100% higher than the value of this parameter in patients with increased activity of the CYP2C19 isoenzyme. Mean C_max values in plasma in patients with reduced isoenzyme activity are increased by approximately 60%. These features do not affect the dose and method of administration of Vimovo^®.

Gender. After a single dose of esomeprazole 40 mg, the mean AUC is 30% higher in women than in men. After repeated administration of esomeprazole once daily, no gender-related differences were identified. These data are not significant for the dosing regimen of Vimovo^®.

Indications

• For the relief of symptoms in the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis in patients at risk of developing gastric and/or duodenal ulcers associated with NSAID use.

ICD codes

Dosage Regimen

The drug is administered orally, 1 tablet (500 mg/20 mg) twice a day. It is recommended to take Vimovo^® at least 30 minutes before meals.

The tablet should be swallowed whole with water, without chewing, breaking in half, or crushing.

Patients with mild to moderate renal impairment should be prescribed Vimovo^® with caution and under close monitoring of renal function. A reduction in the daily dose of naproxen may be required. If a daily naproxen dose of 1000 mg is not acceptable, alternative treatment regimens should be used. The use of the drug is contraindicated in patients with severe renal impairment (CrCl < 30 ml/min) due to the observed accumulation of naproxen metabolites in this category of patients and in patients on hemodialysis.

Patients with mild or moderate hepatic impairment should be prescribed Vimovo^® with caution and under close monitoring of liver function. A reduction in the daily dose of naproxen may be required. If a daily naproxen dose of 1000 mg is not acceptable, alternative treatment regimens should be used. Vimovo^® is contraindicated in patients with severe hepatic impairment, as these patients are not recommended to take more than 20 mg of esomeprazole per day.

Elderly patients have an increased risk of developing serious complications from adverse reactions.

Adverse Reactions

The drug Vimovo^® contains Naproxen and Esomeprazole, so the same adverse effects that were observed with the use of these active substances separately may develop. Gastrointestinal adverse effects, such as dyspepsia, stomach pain, nausea, and vomiting, are most common with naproxen use. In the development of Vimovo^®, Esomeprazole was included in its composition to reduce the frequency of naproxen-associated gastrointestinal side effects. It has been shown that taking Vimovo^® significantly reduced the incidence of gastric ulcerative lesions and upper gastrointestinal adverse events associated with NSAIDs compared with naproxen monotherapy.

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

No differences in the types of adverse reactions were established with the use of the drug for 12 months compared to short-term therapy. Patients taking Vimovo^® discontinued therapy prematurely due to adverse reactions significantly less frequently compared to patients taking enteric-coated Naproxen alone (7.9% compared to 12.5%, respectively). The proportion of patients who discontinued treatment due to any upper gastrointestinal adverse event (including duodenal ulcers) with Vimovo^® was 4% compared to 12% of patients receiving enteric-coated Naproxen alone. Adverse reactions are classified by frequency of occurrence and by organs and systems. Definition of adverse reaction frequency: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000); unknown (cannot be estimated from the available data).

Naproxen

Table 1 presents adverse reactions noted in patients receiving Naproxen during clinical studies and the post-marketing period.

Table 1.

Esomeprazole

Table 2 presents adverse reactions that were identified or suspected in patients receiving enteric-coated Esomeprazole during clinical studies and/or the post-marketing period. None of these adverse reactions were dose-dependent.

Table 2.

Vimovo^® contains methyl and propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed-type).

Contraindications

• History of bronchial asthma, urticaria, and allergic reactions when taking acetylsalicylic acid and other NSAIDs (complete or incomplete combination of acetylsalicylic acid intolerance, rhinosinusitis, urticaria/angioedema, nasal mucosal polyposis, and bronchial asthma);
• Severe hepatic failure (Child-Pugh class C) or active liver disease;
• Severe renal failure (CrCl less than 30 ml/min);
• Severe uncontrolled heart failure;
• Confirmed hyperkalemia;
• Peptic ulcer of the stomach or duodenum in the acute phase;
• Gastrointestinal bleeding, cerebral hemorrhage, or other bleeding;
• Inflammatory bowel disease in the acute phase (ulcerative colitis, Crohn’s disease);
• Conditions after coronary artery bypass graft surgery;
• Concomitant use with atazanavir and nelfinavir;
• Third trimester of pregnancy;
• Breastfeeding period;
• Children and adolescents under 18 years of age (efficacy and safety of use have not been studied);
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other substituted benzimidazoles.

With caution chronic heart failure (NYHA functional class II-IV); history of gastrointestinal side effects when taking acetylsalicylic acid or NSAIDs; arterial hypertension; coronary artery disease; peripheral arterial disease; cerebrovascular accident; concomitant use of oral corticosteroids, anticoagulants, selective serotonin reuptake inhibitors or antithrombotic agents (e.g., acetylsalicylic acid), ACE inhibitors, diuretics; patients with risk factors for cardiovascular diseases (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking); history of gastrointestinal diseases (Crohn’s disease, ulcerative colitis); hypovolemia; moderate and severe renal impairment; mild and moderate hepatic impairment; elderly patients.

Use in Pregnancy and Lactation

Pregnancy

Naproxen. Studies of naproxen in animals have not revealed direct or indirect adverse effects on embryo/fetal development. Congenital anomalies have been noted with the use of NSAIDs in humans; however, they developed rarely and were not specific. As with other drugs of this type, Naproxen inhibits labor in animals and affects the fetal cardiovascular system (premature closure of the ductus arteriosus). The use of naproxen is contraindicated in the third trimester of pregnancy. NSAIDs should not be prescribed during the first and second trimesters of pregnancy, except in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Drugs containing Naproxen are not recommended for use during labor and delivery due to naproxen’s suppression of prostaglandin synthesis; Naproxen may adversely affect fetal circulation and inhibit labor, increasing bleeding in the mother and child.

Esomeprazole. Clinical data on the effect of esomeprazole on pregnancy are insufficient. In animal studies, Esomeprazole did not have direct or indirect adverse effects on embryo/fetal development. In animal studies, the racemic mixture did not have direct or indirect adverse effects on pregnancy, childbirth, or postnatal development. Esomeprazole should be prescribed to pregnant women with caution.

Breastfeeding

Naproxen is excreted in human breast milk. It is not known whether Esomeprazole is excreted in breast milk, as studies in lactating women have not been conducted. The use of the drug Vimovo^® is contraindicated during breastfeeding.

Use in Hepatic Impairment

Patients with mild or moderate hepatic impairment should be prescribed Vimovo^® with caution and under close monitoring of liver function. A reduction in the daily dose of naproxen may be required. If a daily naproxen dose of 1000 mg is not acceptable, alternative treatment regimens should be used. Vimovo^® is contraindicated in patients with severe hepatic impairment, as these patients are not recommended to take more than 20 mg of esomeprazole per day.

Use in Renal Impairment

Patients with mild to moderate renal impairment should be prescribed Vimovo^® with caution and under close monitoring of renal function. A reduction in the daily dose of naproxen may be required. If a daily naproxen dose of 1000 mg is not acceptable, alternative treatment regimens should be used. The use of the drug is contraindicated in patients with severe renal impairment (CrCl < 30 ml/min) due to the observed accumulation of naproxen metabolites in this category of patients and in patients on hemodialysis.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Elderly patients have an increased risk of developing serious complications from adverse reactions.

Special Precautions

Elderly patients

Naproxen. Elderly patients have shown an increased frequency of adverse reactions with NSAID use, particularly gastrointestinal bleeding, ulcerative lesions, and gastrointestinal perforation, which can be fatal. In clinical studies of Vimovo^®, elderly patients did not show an increased incidence of gastric and duodenal ulcers compared to patients younger than 60 years; the reduction in the risk of ulcer development was maintained in this elderly population. However, ulcer complications such as bleeding, perforation, and gastrointestinal obstruction were not studied in these Vimovo^® studies.

Effect on the Gastrointestinal Tract

Naproxen. Gastrointestinal bleeding, ulceration, or perforation, which can be fatal, have been observed with all NSAIDs at any time during treatment, with or without warning symptoms, in patients with or without a history of serious gastrointestinal events. Vimovo^® contains Esomeprazole to reduce the frequency of naproxen-associated gastrointestinal side effects, including ulceration. Although Vimovo^® significantly reduces the incidence of gastric ulcers compared to naproxen alone, the development of ulcers and associated complications is still possible.

The risk of gastrointestinal bleeding, ulceration, and perforation with NSAID use increases with higher doses of naproxen in patients with a history of peptic ulcer disease, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should be started on therapy at the lowest dose. Patients with a history of gastrointestinal adverse reactions; especially elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) and, particularly, at the beginning of treatment. NSAIDs should be prescribed with caution to patients already taking medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants, e.g., warfarin, selective serotonin reuptake inhibitors, or antithrombotic agents such as acetylsalicylic acid.

If gastrointestinal bleeding or an ulcer develops, the use of Vimovo^® must be discontinued.

NSAIDs should be prescribed with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) due to the possible exacerbation of this disease.

Esomeprazole. If any alarming symptom develops (e.g., significant, unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) and if a gastric ulcer is suspected or confirmed, a malignant neoplasm must be ruled out, as esomeprazole magnesium may alleviate symptoms and delay diagnosis. Proton pump inhibitor therapy may slightly increase the risk of gastrointestinal infections with microorganisms such as Salmonella and Campylobacter.

Effect on the cardiovascular system and cerebral circulation

Naproxen. As with the use of any NSAID, patients with a history of arterial hypertension and/or chronic heart failure should be monitored, as NSAID therapy is accompanied by fluid retention and the development of edema.

Naproxen should be prescribed to patients with uncontrolled arterial hypertension, chronic heart failure, coronary artery disease, peripheral arterial disease, and/or cerebrovascular disorders only after a thorough examination. The same examination should be performed before initiating long-term therapy in patients with risk factors for cardiovascular diseases (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

According to clinical and epidemiological studies, therapy with naproxen (1000 mg/day) may be associated with a lower risk of arterial thrombosis than selective COX-2 inhibitors, but this small risk cannot be ruled out. Overall, the data do not support a cardioprotective effect.

Effect on the kidneys

Naproxen. Long-term use of NSAIDs has led to the development of renal medullary necrosis and other renal injuries. Renal toxicity has also been observed in patients in whom renal prostaglandins played a compensatory role in maintaining renal perfusion. In these patients, the use of NSAIDs may lead to a dose-dependent reduction in prostaglandin synthesis, and subsequently to a decrease in renal blood flow, which may accelerate the development of renal failure with clinical manifestations. The highest risk of such a reaction is present in patients with impaired renal function, hypovolemia, heart failure, hepatic insufficiency, excessive sodium chloride excretion, patients receiving diuretics and ACE inhibitors, and elderly patients. After discontinuation of NSAID therapy, the patients’ condition usually returns to the pre-treatment level.

Use in patients with renal insufficiency

Since Naproxen is excreted to a greater extent (95%) by renal excretion via glomerular filtration, it should be prescribed with great caution to patients with renal insufficiency, and it is recommended to monitor serum creatinine levels and/or creatinine clearance in these patients. Vimovo^® is not recommended for patients with a baseline creatinine clearance of less than 30 ml/min. Hemodialysis does not reduce the plasma concentration of naproxen due to its high binding to plasma proteins. Renal function should be assessed in certain patients, especially those with impaired renal blood flow due to reduced extracellular fluid volume, liver cirrhosis, salt restriction, chronic heart failure, and pre-existing renal disease, before and during Vimovo^® administration. Some elderly patients with presumed impaired renal function, as well as patients receiving diuretics, may also fall into this category. To prevent possible excessive accumulation of naproxen metabolites in these patients, the daily dose of the drug should be reduced.

Effect on the hematopoietic system

Naproxen. Preparations containing Naproxen should be prescribed with caution to patients with coagulation disorders or those receiving therapy affecting hemostasis. The risk of bleeding in such patients at high risk of bleeding or receiving full anticoagulant therapy (e.g., dicumarol derivatives) increases with the concomitant use of preparations containing Naproxen. Naproxen reduces platelet aggregation and prolongs bleeding time. This should be taken into account when determining bleeding time.

If active or clinically significant bleeding develops in any area in patients taking Vimovo^®, therapy should be discontinued.

Dermatological effects

Naproxen. Very rarely, serious skin reactions have developed with the use of NSAIDs, some of which have led to patient death, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk of such reactions exists at the beginning of therapy, and in most cases, the onset of such reactions occurs within the first month of treatment. At the first signs of skin rash, mucosal lesions, or other symptoms of hypersensitivity, Vimovo^® should be discontinued.

Effect on visual function

If visual disturbances occur while taking Vimovo^®, an ophthalmologist consultation is recommended.

Anaphylactic (anaphylactoid) reactions

Naproxen. Hypersensitivity reactions may develop in predisposed patients. Anaphylactic (anaphylactoid) reactions may develop in patients with or without a history of hypersensitivity, or with or without hypersensitivity to acetylsalicylic acid, other NSAIDs, or preparations containing Naproxen. These reactions may develop in patients with a history of angioedema, bronchospasm (e.g., bronchial asthma), rhinitis, and polypoid rhinosinusopathy.

Patients with bronchial asthma

Naproxen. The use of acetylsalicylic acid in patients with aspirin asthma has been accompanied by the development of severe bronchospasm, which can lead to patient death. Since cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs has been noted in patients with hypersensitivity to acetylsalicylic acid, Vimovo^® is not recommended for patients with such hypersensitivity to acetylsalicylic acid and should be prescribed with caution to patients with bronchial asthma.

Inflammation

Naproxen. The antipyretic and anti-inflammatory properties of naproxen may reduce fever and other signs of inflammation, thereby reducing their significance as diagnostic symptoms.

Combinations with other drugs

Naproxen. Naproxen is not recommended to be used concomitantly with NSAIDs (except for acetylsalicylic acid), including selective COX-2 inhibitors, due to the cumulative risk of developing serious adverse events associated with NSAIDs.

General instructions

If a daily dose of naproxen of 1000 mg is not acceptable, alternative treatment regimens should be used.

Patients receiving long-term therapy (especially more than 1 year) should be under constant supervision.

Effect on the ability to drive vehicles and operate machinery

Since dizziness, visual disturbances, and drowsiness may be observed during therapy with Vimovo^®, caution should be exercised when driving vehicles and operating other machinery.

Overdose

There is no data on Vimovo^® overdose. Any effects of Vimovo^® overdose will mainly reflect the effects of naproxen overdose.

Symptoms

Naproxen. In cases of clinically significant naproxen overdose, lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient changes in liver function, hypoprothrombinemia, impaired renal function, metabolic acidosis, apnea, disorientation, or vomiting, gastrointestinal bleeding may occur. In rarer cases – increased blood pressure, acute renal failure, respiratory failure, and coma. Seizures have been observed in some patients, but a causal relationship with the drug has not been reliably established. It is also unknown what dose of the drug will be life-threatening.

Esomeprazole. Symptoms of intentional esomeprazole overdose (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 gastrointestinal symptoms. No overdose was observed with a single dose of esomeprazole 80 mg.

Treatment

Naproxen. After an NSAID overdose, symptomatic and supportive therapy should be provided, especially if gastrointestinal effects and renal damage develop. There are no specific antidotes. Hemodialysis does not reduce the plasma concentration of naproxen due to its high degree of binding to plasma proteins. Induction of vomiting and/or administration of activated charcoal (60-100 g for adult patients, 1-2 g/kg for children) and/or use of an osmotic laxative may be prescribed to patients 4 hours after drug intake if symptoms are present or after a significant overdose. Forced diuresis, urine alkalinization, or hemoperfusion are not effective due to the high binding of the drug to plasma proteins.

Esomeprazole. No specific antidote is known. Esomeprazole is highly bound to plasma proteins, so it is not removed by hemodialysis. In case of esomeprazole overdose, symptomatic and supportive therapy should be provided.

Drug Interactions

Not recommended combinations

Antiretroviral drugs. It has been shown that omeprazole, and its racemate Esomeprazole, interact with some antiretroviral drugs. The clinical significance and mechanisms of this interaction are not fully understood. The increase in gastric pH during omeprazole administration may alter the absorption of the antiretroviral drug. Other possible mechanisms of interaction are mediated by the CYP2C19 isoenzyme. When some antiretroviral drugs, such as atazanavir and nelfinavir, were used concomitantly with omeprazole, the serum concentrations of these drugs decreased. Therefore, it is not recommended to take omeprazole concomitantly with drugs such as atazanavir and nelfinavir. When omeprazole was used concomitantly with other antiretroviral drugs, such as saquinavir, an increase in the serum concentration of the latter was noted. The serum concentrations of some other antiretroviral drugs did not change with concomitant use with omeprazole. Due to the similarity of the pharmacodynamic and pharmacokinetic properties of omeprazole and esomeprazole, the administration of esomeprazole concomitantly with antiretroviral drugs such as atazanavir and nelfinavir is contraindicated.

Use with caution

Acetylsalicylic acid. Vimovo^® can be taken concomitantly with low-dose acetylsalicylic acid (≤325 mg/day). In clinical studies, the incidence of gastric ulcers in patients taking Vimovo^® in combination with low-dose acetylsalicylic acid did not increase compared to patients receiving Vimovo^® alone. However, concomitant use of acetylsalicylic acid and Vimovo^® may increase the risk of serious adverse effects.

When naproxen is used concomitantly with high doses of acetylsalicylic acid, its binding to plasma proteins decreases, but without affecting the clearance of free naproxen. The clinical significance of this interaction is unknown.

Diuretics. Clinical studies, as well as post-marketing surveillance, have shown that in some patients, NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics. This is due to the suppression of prostaglandin synthesis in the kidneys. When using diuretics with NSAIDs, patients should be carefully monitored for signs of renal failure, and the effectiveness of diuretic therapy should be controlled.

Selective serotonin reuptake inhibitors. According to epidemiological studies, there is an association between the use of psychotropic drugs that affect serotonin reuptake and the development of upper gastrointestinal bleeding. Therefore, NSAIDs, including selective COX-2 inhibitors, should be prescribed with caution concomitantly with selective serotonin reuptake inhibitors.

Corticosteroids. Concomitant use of corticosteroids with NSAIDs, including selective COX-2 inhibitors, increases the risk of gastrointestinal bleeding. NSAIDs should be prescribed with caution concomitantly with corticosteroids.

ACE inhibitors. NSAIDs can reduce the antihypertensive effect of ACE inhibitors. This interaction should be taken into account when prescribing NSAIDs concomitantly with ACE inhibitors.

Lithium preparations. NSAIDs increase the plasma concentration of lithium and reduce the renal clearance of lithium. The mean C_min of lithium increases by 15%, and renal clearance decreases by 20%. These effects were due to the inhibition of prostaglandin synthesis in the kidneys under the influence of NSAIDs. Therefore, when NSAIDs and lithium preparations are used concomitantly, signs of lithium toxicity should be carefully monitored.

Methotrexate. NSAIDs competitively inhibit the accumulation of methotrexate and reduce the secretion of methotrexate in the renal tubules in an animal model. This may indicate a possible increase in methotrexate toxicity when used concomitantly with NSAIDs. In this regard, caution should be exercised when using NSAIDs and methotrexate concomitantly.

Sulfonylurea derivatives, hydantoins. Naproxen is highly bound to plasma albumin, so interaction with other albumin-binding drugs, such as sulfonylurea derivatives and hydantoins, is theoretically possible. The dose of the drug should be adjusted if necessary in patients receiving Naproxen and hydantoin derivatives, sulfonamides, or sulfonylurea derivatives concomitantly.

Warfarin. NSAIDs may enhance the effect of oral anticoagulants (e.g., warfarin and acenocoumarol) and heparin. When esomeprazole 40 mg was used concomitantly with warfarin, despite a slight increase in C_min in plasma of the less potent R-isomer of warfarin, the coagulation time remained within the acceptable range. However, post-marketing surveillance has identified cases of clinically significant increases in INR with concomitant use with warfarin. Therefore, careful monitoring is recommended during the initiation and termination 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.

Cyclosporine/tacrolimus. Due to the increased risk of nephrotoxicity, caution should be exercised when taking cyclosporine or tacrolimus concomitantly with any NSAIDs.

Probenecid. Concomitant therapy with probenecid increases the plasma concentration of the naproxen anion and significantly prolongs T_1/2 from plasma.

Drugs whose absorption depends on gastric pH. Reduced gastric acidity during esomeprazole use may increase or decrease the absorption of drugs if the absorption mechanism of these drugs is dependent on gastric acidity. As with the use of other drugs that suppress hydrochloric acid secretion or antacids, treatment with esomeprazole may lead to reduced absorption of ketoconazole or itraconazole, as well as increased absorption of digoxin. Concomitant administration of omeprazole 20 mg once daily and digoxin increased the bioavailability of digoxin by 10% (the bioavailability of digoxin increased by up to 30% in 20% of patients).

Drug interactions with other drugs

Studies of the concomitant use of esomeprazole and naproxen (a non-selective NSAID) or rofecoxib (a selective COX-2 inhibitor) did not reveal clinically significant interactions.

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

Esomeprazole inhibits CYP2C19, the main isoenzyme involved in the metabolism of esomeprazole. Esomeprazole is also metabolized by the CYP3A4 enzyme. The following data are available regarding CYP2C19-, CYP3A4-mediated interactions

• Concomitant use of esomeprazole 30 mg reduces the clearance of diazepam, a CYP2C19 substrate, by 45% (this interaction is unlikely to be of clinical significance).
• Concomitant use of esomeprazole 40 mg increases the C_min of phenytoin in plasma by 13% in patients with epilepsy.
• Concomitant use of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may nearly double the concentration of esomeprazole;
• Concomitant use of Esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily), doubles the AUC of esomeprazole.

No dose adjustment of esomeprazole is required in these cases.

Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St. John’s wort preparations, when used concomitantly with esomeprazole, may lead to a decrease in the plasma concentration of esomeprazole due to accelerated metabolism of esomeprazole.

Effect on laboratory parameters

Naproxen may reduce platelet aggregation and prolong bleeding time. This should be kept in mind when determining bleeding time.

Naproxen may increase urinary 17-ketosteroid levels when measured due to the interaction of the drug and/or its metabolites with m-dinitrobenzene used in this assay. Although 17-hydroxycorticosteroid measurements (Porter-Silber test) were not altered, naproxen therapy was temporarily discontinued for 72 hours before performing tests to assess adrenal function if the Porter-Silber test was used.

Naproxen may interact with some substances used in the urine test for 5-hydroxyindoleacetic acid.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging, in a tightly closed bottle to protect from moisture, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.