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. 2010 Sep;35(9 Section 2):2–4.

Vimovo™: (naproxen/esomeprazole magnesium) delayed-release tablets

PMCID: PMC2957726  PMID: 20975802

INTRODUCTION

This Product Profiler introduces health care providers to VIMOVO (naproxen and esomeprazole magnesium), a U.S. Food and Drug Administration–approved treatment indicated for the relief of signs and symptoms of osteoarthritis (OA) rheumatoid arthritis (RA), and ankylosing spondylitis (AS) and to decrease the risk of developing gastric ulcers in patients at risk for developing non-steroidal anti-inflammatory drug (NSAID)-associated gastric ulcers (Please see full indication in grey box).

OA is the most common type of arthritis and it has a high prevalence rate in the elderly. It can be mild or can have devastating and debilitating effects and can readily impact the lifestyles of those suffering from the disease. The physical findings common with this disease also play an important role in the loss of function and subsequent disability that may result.

The following text presents a brief overview of the pathophysiology and clinical features of OA, and the pharmacology, efficacy, and safety profile of VIMOVO.

Disease Overview

The components of a healthy joint are paramount to the normal, healthy functioning of patients. However, when a disease process occurs, it can cause severe and detrimental effects to specific areas of the body. In this case, OA causes substantial changes in normally functioning joints ultimately leading to compromised joint function.

Pathophysiology

Components of a healthy functioning joint. The components of a normally functioning synovial joint include the articular cartilage, joint capsule, and synovial membrane (Shier 2010) (Figure 1). The bones in the synovial joint are covered with a layer of cartilage that functions to resist wear and minimize friction when the joint is in use (Shier 2010). Another component is the joint capsule. The joint capsule attaches to each end of the bone and encloses the synovial joint (Shier 2010). The joint capsule, made up of dense connective tissue, and ligaments serve to reinforce the joint, prevent excessive movement, and allow relative joint flexibility necessary for use (Shier 2010).

FIGURE 1.

FIGURE 1

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Source: Adapted from Shier 2010.

Some joints, such as the knee joint, are partially or completely divided by discs of fibrocartilage called meniscus. The meniscus is attached to the fibrous layer of the joint capsule, cushioning the articulating surfaces of the joint and functioning to distribute body weight (Shier 2010).

Another major component of a normal functioning joint is the synovial membrane, which coats the surfaces not covered by the articular cartilage. Functionality of the synovial membrane includes the secretion of synovial fluid, which supplies cartilage with nutrients, and reduces friction between articulating cartilage surfaces via lubrication (Felson 2008, Shier 2010).

Joint failure in OA. The ultimate failure of a joint associated with OA can be attributed to pathological changes in the joint components (Felson 2008). Two such significant changes are in the articulate cartilage and synovial fluid properties. Under healthy conditions, the articulate cartilage within the joint is metabolically sluggish (Felson 2008). In this respect, there is a slow rate of matrix turnover that yields a steady balance between synthesis and degradation of the cartilage matrix (Felson 2008). In early OA, the cartilage matrix becomes metabolically active which leads to an increased release of degradation enzymes, a loosening of the normally tightly woven collagen matrix, and a loss of type 2 collagen, the component that provides cartilage with its tensile strength (Felson 2008). As the articular cartilage softens and disintegrates, the bone no longer has the protective effect of the cartilage (Shier 2010). The bones are left to rub against one another, causing some of the pain and stiffness in the joint (Shier 2010) (Figure 2).

FIGURE 2.

FIGURE 2

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Source: Adapted from Shier 2010.

VIMOVO is indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers.VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months.

Another result of OA are the changes that occur in the synovial fluid. Synovial fluid typically has the consistency of a viscous fluid, similar to that of an uncooked egg white (Shier 2010). The lubricating function of the synovial fluid is due to a mucinous glycoprotein called lubricin (Felson 2008). In the face of a joint injury or during synovial inflammation, the concentration of this much-needed lubricin is diminished (Felson 2008).

Additional pathological changes in the joint. As a direct result of cartilage deterioration in the bone, morphological changes can occur in the subchondral bone (Felson 2008). Bone formation, due to the activation of osteoclasts and osteoblasts in the subchondral bony plate, leads to thickening and sclerosis of the subchondral bone even before the cartilage is completely deteriorated (Felson 2008). In addition, osteophytes, or bony spurs, may form near the margin of the joint or near the areas of cartilage disintegration and loss (Felson 2008). The presence of osteophytes is a hallmark radiographic symptom of OA (Felson 2008).

Additional changes commonly seen as a result of OA that also may contribute to the ultimate failure of a joint include (Felson 2008):

  • Stretching of the articular capsule

  • Mild inflammation of the synovium

  • Muscle weakness supporting the affected joint

  • Deterioration of the meniscus specific to knee joints

Clinical Features

The presence of pain in the joints often is one of the first signs of OA. Pain in a joint often may come on episodically, occurring either during or after joint use and then gradually resolving (Felson 2008). As the disease becomes more advanced, the presence of pain is more continuous in nature and may begin to cause patients discomfort at night (Felson 2008).

Pain experienced from OA is not a direct result of the disintegration of articular cartilage. Cartilage is aneural and, as such, damage or destruction of cartilage does not result in pain (Felson 2008). However, the surrounding structures are innervated and this results in the manifestation of pain (Felson 2008). Disease, dysfunction, over-use, or trauma to any of the components of the joint (eg, synovium, etc.) may cause pain that then warrants further investigations into the possible diagnosis of OA or other arthritis-related disease.

VIMOVO is contraindicated in patients with known hypersensitivity to any component of VIMOVO or substituted benzimidazoles; in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; in patients during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery; or in patients in the late stages of pregnancy.

OA can affect different joints in the body but is most likely to affect the hands, knees, hips, and spine (NIAMS 2006).

Prevalence

OA is the most common type of arthritis and often is more prevalent among older individuals (NIAMS 2006). Although found in both men and women, the latter are more prone to OA of the hands and knees when they approach and pass 50 years of age (Lawrence 2008). OA primarily affects people as they age, however, those as young as 25 can have active symptoms, usually as the result of a joint injury, joint malformation, or genetic defect (NIAMS 2006). In the United States, it is estimated that almost 27 million people aged 25 years and older suffer from OA in at least one joint (Lawrence 2008). Naturally, as the population ages, the number of patients affected with OA will continue to increase (NIAMS 2006). By the year 2030, approximately 72 million or 20% of Americans will be at risk for developing the disease (NIAMS 2006).

Risk Factors

The actual cause of OA is unknown (NIAMS 2009). However, there are a number of risk factors that may be associated with its development. Age is the most probable risk factor since the prevalence and incidence of OA substantially increases with age (Felson 2008). Other factors thought to contribute to OA include (Felson 2008, NIAMS 2009):

  • Female gender

  • Genetic abnormalities

  • Improper joint formation

  • Joint injury

  • Stress from repeated joint use (sports or certain working conditions)

  • Obesity

Nonpharmacologic Treatment Options

Although there is no known prevention for developing OA, there are methods available that can enhance the treatment and subsequent lifestyle in managing patients with OA. Successful treatments for OA often employ a combination of strategies that are tailored specifically to the individual’s needs, lifestyle, and health (NIAMS 2006). Many programs focus attention on managing pain and improving patient functionality. This approach falls in line with the overall goals of OA treatment which include improving joint function, keeping a healthy body weight, controlling/managing pain, and achieving a healthy lifestyle. Nonpharmacologic approaches to OA treatment are further reviewed in Table 1.

TABLE 1.

Non-drug related approaches to OA therapy

Treatment Response
Exercise Improves mood outlook
Decreases pain
Increases flexibility
Improves cardiovascular functioning
Maintains weight
Promotes general physical fitness
Weight decrease Decreases pain in weight bearing joints
Limits further injury
Increases mobility
Rest and joint care Prevents pain from overexertion
Use of heat and/or cold Improves pain relief
Surgery Relieves pain and disability by removing loose pieces of bone and cartilage, repositioning and/or resurfacing bones
Good-health attitude The implementation and encouragement of patient involvement often helps patients manage their symptoms. These areas could include:

  • Patient education

  • Arthritis self-management programs

  • Arthritis support groups
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Sources: NIAMS 2006 and NIAMS 2009

P T. 2010 Sep;35(9):5–8.

Product Information*

INDICATIONS AND USAGE

VIMOVO is a combination product that contains naproxen and esomeprazole. It is indicated for the relief of signs and symptoms of OA, RA, and AS and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers. VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months.

Description

The active ingredients of VIMOVO are naproxen, which is an NSAID and esomeprazole magnesium, which is a Proton Pump Inhibitor (PPI).

VIMOVO is available as an oval, yellow, multi-layer, delayed-release tablet combining an enteric-coated naproxen core and an immediate-release esomeprazole magnesium layer surrounding the core. Each strength contains either 375 mg of naproxen and 20 mg of esomeprazole (present as 22.3 mg esomeprazole magnesium trihydrate) or 500 mg of naproxen and 20 mg of esomeprazole (present as 22.3 mg esomeprazole magnesium trihydrate) for oral administration. The inactive ingredients are carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxide yellow, glyceryl monostearate, hypromellose, iron oxide black, magnesium stearate, methacrylic acid copolymer dispersion, methylparaben, polysorbate 80, polydextrose, polyethylene glycol, povidone, propylene glycol, propylparaben, titanium dioxide, and triethyl citrate.

The chemical name for naproxen is (S)-6-methoxy-α-methyl2-naphthaleneacetic acid. Naproxen’s structure is shown in Figure 3.

FIGURE 3.

FIGURE 3

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Structural Formula for Naproxen

Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3.

Naproxen is an odorless, white to off-white crystalline substance. It is lipid soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8.

The chemical name for esomeprazole is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R-isomers. Its molecular formula is (C17H18N3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. Esomeprazole’s structural formula is shown in Figure 4.

FIGURE 4.

FIGURE 4

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Structural Formula for Esomeprazole

The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water.

The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.

Clinical Pharmacology

Mechanism of Action

VIMOVO consists of an immediate-release esomeprazole magnesium layer and an enteric-coated naproxen core. As a result, esomeprazole is released first in the stomach, prior to the dissolution of naproxen in the small intestine. The enteric coating prevents naproxen release at pH levels below 5.5.

VIMOVO is contraindicated in patients with known hypersensitivity to any component of VIMOVO or substituted benzimidazoles; in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; in patients during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery; or in patients in the late stages of pregnancy.

Naproxen is a NSAID with analgesic and antipyretic properties. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 mg to 40 mg and leads to inhibition of gastric acid secretion.

Pharmacodynamics

Antisecretory Activity

The effect of VIMOVO on intragastric pH was determined in 25 healthy volunteers in one study. Three VIMOVO combinations (naproxen 500 mg combined with either esomeprazole 10 mg, 20 mg, or 30 mg) were administered twice daily over 9 days (Table 2).

TABLE 2.

Effect on Intragastric pH on Day 9 (N=25)

Naproxen 500 mg combined with esomeprazole
10 mg 20 mg 30 mg
% Time Gastric pH>4† 41.1 (3.0) 71.5 (3.0) 76.8 (3.0)
Coefficient of variation 55% 18% 16%
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†

Gastric pH was measured over a 24-hour period

LS Mean (SE)

Serum Gastrin Effects

The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6–12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within 2–3 months of therapy and returned to baseline levels within 4 weeks after discontinuation of therapy.

Enterochromaffin-like (ECL) Cell Effects

In over 1,000 patients treated with esomeprazole (10, 20 or 40 mg/day) up to 6–12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.

Endocrine Effects

Esomeprazole had no effect on thyroid function when given in oral doses of 20 mg or 40 mg for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 mg or 40 mg for 2–4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

Pharmacokinetics

Absorption

Naproxen

At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average, 3 hours following both the morning and the evening dose.

Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses.

Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%.

Steady-state levels of naproxen are reached in 4–5 days.

Esomeprazole

Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO.

Figure 5 represents the pharmacokinetics of naproxen and esomeprazole following administration of a single dose of VIMOVO 500 mg/20 mg.

FIGURE 5.

FIGURE 5

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Mean plasma concentrations of naproxen and esomeprazole following single-dose administration of VIMOVO (500 mg/20 mg)

Food effect

Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (Cmax) by about 12%.

Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax), respectively.

Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (Cmax) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions.

Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and Cmax by 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher Cmax.

Therefore, VIMOVO should be taken at least 30 minutes before the meal.

Distribution

Naproxen

Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500 mg, 1000 mg, and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma.

Esomeprazole

The apparent volume of distribution at steady state in healthy subjects is approximately 16 L. Esomeprazole is 97% plasma protein bound.

Metabolism

Naproxen

Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9, and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half-life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily.

Esomeprazole

Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl-metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.

The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a nonlinear dose-AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time- and dose-dependency.

Excretion

Naproxen

Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.

The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate.

Esomeprazole

Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half life at steady state (1.2–1.5 hours).

Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.

Special Populations

Geriatric Patients

There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients.

The AUC and Cmax values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary.

Race

Pharmacokinetic differences due to race have not been studied for naproxen.

Approximately 3% of Caucasians and 15% to 20% of Asians lacks a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers).

NSAIDs, including VIMOVO, can cause serious GI adverse events, which can be fatal. The risk is greater in patients with a history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. VIMOVO should be used with caution in these patients.

VIMOVO is not recommended in patients with severe hepatic insufficiency. Consider dose reduction in mild/moderate hepatic insufficiency. If abnormal liver enzymes persist or worsen discontinue use immediately.

VIMOVO is not recommended in patients with moderate or severe renal insufficiency. In addition, NSAIDs may cause renal toxicity.

Hepatic Insufficiency

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose.

The AUCs of esomeprazole in patients with severe hepatic insufficiency (Child Pugh Class C) have been shown to be 23 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice-daily dosing.

Renal Insufficiency

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.

Given that naproxen, its metabolites, and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products, including VIMOVO, are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min).

No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

Gender

The AUC and Cmax values of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.

Footnotes

P T. 2010 Sep;35(9):9–15.

Overview of Clinical Trials

The efficacy of VIMOVO was evaluated in 4 clinical studies, 2 of which assessed the incidence of gastric ulcers in patients at risk of developing NSAID-associated ulcers (Study 1 and Study 2) (VIMOVO™ Prescribing Information 2010). The remaining studies (Study 3 and Study 4) evaluated the efficacy of VIMOVO in treatment of the signs and symptoms of OA in patients with osteoarthritis (OA) of the knee. The efficacy of EC naproxen, the nonsteroidal anti-inflammatory component of VIMOVO, to which it is bioequivalent, is well established in the treatment of RA, OA, and AS.

Treatment with VIMOVO 500 mg/20 mg administered twice daily resulted in a statistically significant reduction in the occurrence of gastric ulcers in comparison to enteric-coated (EC) naproxen 500 mg twice daily administered for six months (Study 1 and Study 2).

  • VIMOVO significantly reduced the cumulative incidence of endoscopic gastric ulcers compared to EC-naproxen administered alone after 6 months of treatment (6% vs 24%, respectively; P<.001)

  • Treatment discontinuation due to adverse reactions in Study 1 and Study 2 combined occurred in 7.9% and 12.5% of patients receiving VIMOVO and EC-naproxen, respectively

In patients with OA of the knee, patients receiving VIMOVO achieved significantly better efficacy results compared to a placebo during a 12-week treatment period (Study 3 and 4). Specifically, VIMOVO achieved significant improvement from baseline in Western Ontario MacMaster (WOMAC) pain and function sub-scale scores and Patient Global Assessment (PGA) scores versus a placebo in patients with OA. WOMAC is a self-administered validated instrument specifically designed to assess lower extremity pain and function in OA (Bellamy 2005).

The most common adverse reactions reported in >5% of patients receiving VIMOVO in clinical studies were erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, and nausea.

Gastric Ulcer Formation with VIMOVO in Patients at Risk for NSAID-Associated Gastric Ulcers Compared to EC-Naproxen Alone (Study 1 and Study 2)

Two phase 3, randomized, double-blind, multi-center clinical studies were conducted to assess the gastric ulcer formation with VIMOVO in adult patients (>18 years old) at risk of developing NSAID-associated gastric ulcers (VIMOVO™ Prescribing Information 2010). Study inclusion criteria included the expectation to require daily NSAID therapy for ≥6 months, and in patients < 50 years old, a documented history of gastric or duodenal ulcer within the past 5 years. Patients were randomized to receive VIMOVO 500 mg/20 mg twice daily (n=428), EC-naproxen 500 mg twice daily (n=426), or placebo (n=246) for six months.

VIMOVO resulted in a statistically significant reduction in the incidence of gastric ulcers compared with EC-naproxen alone (Figure 6) at 6 months. Approximately, 25% of patients were receiving concurrent treatment with low-dose (≤325 mg) aspirin. Subgroup analysis revealed similar results in these patients on concomitant low-dose aspirin therapy. The mean duration of treatment was 152 days for the VIMOVO group and 124 days for the EC-naproxen group.

FIGURE 6.

FIGURE 6

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Cumulative Observed Incidence of Gastric Ulcers over 6 Months

The most commonly observed adverse events in clinical trials (experienced by >5% patients in the VIMOVO group) were erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, and nausea.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. VIMOVO can be administered with low-dose aspirin (≤325 mg/day) therapy. The concurrent use of aspirin and VIMOVO may increase the risk of serious adverse events. As with all NSAIDs, concurrent administration of naproxen and aspirin is not generally recommended because of the potential of increased adverse events.

Safety Considerations

The most common adverse reactions reported in ≥10% of patients in either VIMOVO (n=428) or EC-naproxen (n=426) treatment group, respectively, were: erosive gastritis (19%, 38%), dyspepsia (18%, 27%), gastritis (17%, 14%), gastric ulcer (6%, 24%), and erosive duodenitis (2%, 12%) (Table 3) (VIMOVO™ Prescribing Information 2010).

TABLE 3.

Adverse reactions occurring in patients >2% Study 1 and Study 2 (endoscopic studies)

Preferred term (sorted by SOC) VIMOVO 500 mg/20 mg twice daily (n=428); % EC-naproxen 500 mg twice daily (n=426); %
Gastrointestinal disorders
Gastric erosive 19 38
Dyspepsia 18 27
Gastris 17 14
Diarrhea 6 5
Gastric ulcer 6 24
Abdominal pain upper 6 9
Nausea 5 5
Hiatus hernia 4 6
Abdominal distension 4 4
Flatulence 4 3
Esophagitis 4 8
Constipation 3 3
Abdominal pain 2 2
Erosive duodenitis 2 12
Abdominal pain lower 2 3
Duodenitis 1 7
Gastritis hemorrhagic 1 2
Gastroesophageal reflux disease <1 4
Duodenal ulcer <1 5
Erosive esophagitis <1 6
Infections and infestations
Upper respiratory tract
Infection 5 4
Bronchitis 2 2
Urinary tract infection 2 1
Sinusitis 2 2
Nasopharyngitis <1 2
Musculoskeletal and connective tissue disorders
Arthralgia 1 2
Nervous system disorders
Headache 3 1
Dysgeusia 2 1
Respiratory, thoracic, and mediastinal disorders
Cough 2 3
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Premature treatment discontinuation due to adverse reactions occurred in 7.9% of patients treated with VIMOVO and 12.5% of patients receiving EC-naproxen; treatment discontinuations associated with upper GI adverse events, including duodenal ulcer, were 4% and 12%, respectively. The most common discontinuation reasons due to an adverse event are shown in Table 3.

Efficacy of VIMOVO for Treating the Signs and Symptoms of Osteoarthritis of the Knee Compared to Placebo (Study 3 and Study 4)

The efficacy of VIMOVO for treating the signs and symptoms of OA of the knee compared to placebo was studied in two randomized, double-blind, placebo-controlled studies (VIMOVO™ Prescribing Information 2010). Patients were treated with VIMOVO 500 mg/20 mg once daily (n=490) over 12 weeks and assessed for signs and symptoms of OA. The study protocols allowed the concomitant use of low-dose aspirin for cardioprophylaxis.

After 12 weeks of treatment, patients receiving VIMOVO demonstrated a significant improvement from baseline in WOMAC scores and Patient Global Assessment Scores in comparison to placebo.

Safety Considerations

The most common adverse reactions in Study 3 and Study 4 reported in ≥5% of patients in either VIMOVO (n=490) or placebo treatment group (n=246), respectively, were: dyspepsia (8%, 12%), diarrhea (6%, 4%), and headache (3%, 5%), and are shown in Table 4. Treatment discontinuation due to adverse events occurred in 7% of patients receiving VIMOVO.

TABLE 4.

Adverse reactions occurring in patients >2% (Study 3 and Study 4)

Preferred term (sorted by SOC) VIMOVO 500 mg/20 mg twice daily (n=246) % Placebo (n=490) %
Gastrointestinal disorders
Dyspepsia 8 12
Diarrhea 6 4
Abdominal pain upper 4 3
Constipation 4 1
Nausea 4 4
Nervous system disorders
Dizziness 3 2
Headache 3 5
General disorders and administration site conditions
Peripheral edema 3 1
Respiratory, thoracic and mediastinal disorders
Cough 1 3
Infections and infestations
Sinusitis 1 2
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EC-naproxen and Efficacy in Patients with Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

The efficacy of the EC-naproxen component of VIMOVO is well established in patients with RA, OA, and RA (VIMOVO™ Prescribing Information 2010). In clinical studies, treatment with EC-naproxen was effective in reducing joint swelling, duration of morning stiffness, and disease activity while increasing mobility in patients with RA. In patients with OA, naproxen demonstrated a reduction in joint pain or tenderness and an increase in mobility and range of motion in knee joints, as well as improvement in performance of daily activities impaired by the disease. For the treatment of AS, patients receiving naproxen experienced reduction in night pain, morning stiffness, and pain at rest.

SAFETY*

Contraindications

VIMOVO is contraindicated in patients with known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any of the excipients.

VIMOVO is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Hypersensitivity reactions, eg, angioedema and anaphylactic reaction/shock, have been reported with esomeprazole use.

VIMOVO is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

VIMOVO is contraindicated in patients in the late stages of pregnancy.

Warnings and Precautions

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

Hypertension

NSAIDs, including naproxen, a component of VIMOVO, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs and should be used with caution in patients with fluid retention, or heart failure.

Gastrointestinal Effects — Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including naproxen, a component of VIMOVO, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. While VIMOVO has been shown to significantly decrease the occurrence of gastric ulcers compared to naproxen alone, ulceration and associated complications can still occur.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2%–4% of patients treated for 1 year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed.

VIMOVO should be prescribed with caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk of developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants or antiplatelets (including low-dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID or NSAID-containing product, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding. Although these studies focused on upper GI bleeding, bleeding at other sites cannot be ruled out.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Gastrointestinal symptomatic response to therapy with VIMOVO does not preclude the presence of gastric malignancy.

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer and a component of VIMOVO.

Active Bleeding

When active and clinically significant bleeding from any source occurs in patients receiving VIMOVO, the treatment should be withdrawn.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of VIMOVO in patients with advanced renal disease. Therefore, treatment with VIMOVO is not recommended in these patients with advanced renal disease. If VIMOVO therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Anaphylactoid Reactions

Anaphylactoid reactions may occur in patients without known prior exposure to either component of VIMOVO. NSAIDs should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Skin Reactions

NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

Pregnancy Category C

In late pregnancy, as with other NSAIDs, naproxen, a component of VIMOVO should be avoided because it may cause premature closure of the ductus arteriosus.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including naproxen, a component of VIMOVO. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with VIMOVO.

If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc), VIMOVO should be discontinued.

Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose for the shortest possible duration of adequate treatment.

VIMOVO is not recommended in patients with severe hepatic impairment because esomeprazole doses should not exceed 20 mg daily in these patients.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving VIMOVO who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants or antiplatelets, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIMOVO should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Concomitant NSAID Use

VIMOVO contains naproxen as one of its active ingredients. It should not be used with other naproxen-containing products since they all circulate in the plasma as the naproxen anion.

The concomitant use of VIMOVO with any dose of a nonaspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

Corticosteroid Treatment

VIMOVO cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Bone Fracture

Several studies and literature reports indicate that proton pump inhibitor (PPI) therapy is associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Those patients with the highest risk received high-dose or long-term PPI therapy (a year or longer). Patients should use the lowest effective dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. Adequate vitamin D and calcium intake is recommended.

Masking of Inflammation and Fever

The pharmacological activity of VIMOVO in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc) or if abnormal liver tests persist or worsen, VIMOVO should be discontinued.

Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically.

Adverse Reactions

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse reactions reported below are specific to the clinical trials with VIMOVO. See also the full prescribing information for naproxen and esomeprazole magnesium products.

The safety of VIMOVO was evaluated in clinical studies involving 2317 patients (aged 27 to 90 years) and ranging from 3–12 months. Patients received either 500 mg/20 mg of VIMOVO twice daily (n=1157), 500 mg of EC-naproxen twice daily (n=426), or placebo (n=246). The average number of VIMOVO doses taken over 12 months was 696±44.

Table 3 (page 10) lists all adverse reactions, regardless of causality, occurring in >2% of patients receiving VIMOVO from two clinical studies (Study 1 and Study 2). Both of these studies were randomized, multi-center, double-blind, parallel studies. The majority of patients were female (67%), white (86%). The majority of patients were 50–69 years of age (83%). Approximately one quarter were on low-dose aspirin.

In Study 1 and Study 2, patients taking VIMOVO had fewer premature discontinuations due to adverse reactions compared to patients taking EC-naproxen alone (7.9% vs 12.5% respectively). The most common reasons for discontinuations due to adverse events in the VIMOVO treatment group were upper abdominal pain (1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving EC-naproxen, the most common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to any upper GI adverse events (including duodenal ulcers) in patients treated with VIMOVO was 4% compared to 12% for patients taking EC-naproxen.

Table 4 (page 11) lists all adverse reactions, regardless of causality, occurring in >2% of patients from 2 clinical studies conducted in patients with OA of the knee (Study 3 and Study 4).

The percentage of subjects who withdrew from the VIMOVO treatment group in these studies due to treatment emergent adverse events was 7%. There were no preferred terms in which more than 1% of subjects withdrew from any treatment group.

The long-term safety of VIMOVO was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of VIMOVO for 12 months. There were no differences in frequency or types of adverse reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies.

Postmarketing experience

Naproxen

The following adverse reactions have been identified during post-approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system:

Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)

Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema

Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease), nonpeptic gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic ulceration

Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal)

Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia

Metabolic and Nutritional: hyperglycemia, hypoglycemia

Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions

Respiratory: eosinophilic pneumonitis, asthma

Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema

Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine

Reproduction (female): infertility

Esomeprazole

The following adverse reactions have been identified during post-approval use of esomeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system:

Blood And Lymphatic: agranulocytosis, pancytopenia

Eye: blurred vision

Gastrointestinal: pancreatitis; stomatitis

Hepatobiliary: hepatic failure, hepatitis with or without jaundice

Immune System: anaphylactic reaction/shock

Infections and Infestations: GI candidiasis

Metabolism and Nutritional Disorders: hypomagnesemia

Musculoskeletal and Connective Tissue: muscular weakness, myalgia

Nervous System: hepatic encephalopathy, taste disturbance

Psychiatric: aggression, agitation, depression, hallucination

Renal and Urinary: interstitial nephritis

Reproductive System and Breast: gynecomastia

Respiratory, Thoracic, and Mediastinal: bronchospasm

Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal)

Dosage and Administration

Carefully consider the potential benefits and risks of VIMOVO and other treatment options before deciding to use VIMOVO. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. VIMOVO does not allow for administration of a lower daily dose of esomeprazole. If a dose of esomeprazole lower than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.

Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

The dosage is one tablet twice daily of VIMOVO 375 mg naproxen and 20 mg of esomeprazole or 500 mg naproxen and 20 mg of esomeprazole.

The tablets are to be swallowed whole with liquid. Do not split, chew, crush, or dissolve the tablet. VIMOVO is to be taken at least 30 minutes before meals.

Geriatric Patients

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly use the lowest effective dose.

Patients With Moderate to Severe Renal Impairment

Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance <30 mL/min).

Hepatic Insufficiency

Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose reduction based on the naproxen component of VIMOVO.

VIMOVO is not recommended in patients with severe hepatic impairment because esomeprazole doses should not exceed 20 mg daily in these patients.

Pediatric Patients

The safety and efficacy of VIMOVO in children younger than 18 years has not been established. VIMOVO is therefore not recommended for use in children.

How Supplied/Storage and Handling

VIMOVO 375 mg/20 mg tablets are oval, yellow film-coated tablets printed with 375/20 in black ink, supplied as:
NDC 0186-0510-60 Bottles of 60 tablets
VIMOVO 500 mg/20 mg tablets are oval, yellow film-coated tablets printed with 500/20 in black ink, supplied as:
NDC 0186-0520-60 Bottles of 60 tablets
NDC 0186-0520-39 Unit Dose Blisters, package of 100 tablets
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Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided.

The lowest effective dose for the shortest duration is recommended based on the individual treatment goals.

Footnotes

P T. 2010 Sep;35(9):16–18.

P&T Committee Considerations

P&T decision makers must explore various aspects of a drug product when considering its place on a formulary. Points of interest often include: efficacy, safety, availability of alternative agents, and cost. This section evaluates P&T considerations that apply to VIMOVO.

Economic Considerations

OA is a degenerative, chronic disease that has enormous health, social, and economic implications. Early diagnosis and medical management is the first step in successful management of OA.

A continued upward trend in the rising cost for total medical expenditures for arthritis and other rheumatic conditions in the United States was estimated in 1997 to be $233.5 billion (Yelin 2007). By 2003, these costs had increased to $321.8 billion after factoring in inflation. A substantial part of these costs are specifically related to OA. One estimate by Leigh et al. put the total annual costs of OA at 89.1 billion (Leigh 2001).

Studies have found that the direct costs of OA are somewhat heterogeneous, a result of varying patient populations, payers, calculated variables, and treatment locations (Bitton 2009).

When selecting an agent for the management of the OA patient, physicians must weight both the benefits and the risks of its administration (Lanza 2009). Treatment guidelines developed by the American College of Gastroenterology recommend concurrent administration of proton pump inhibitors or misoprostol as a gastroprotective agent in patients with low cardiovascular risk with at least two GI risk factors or in patients with high cardiovascular risk (low-dose aspirin required) or in patients with high cardiovascular risk (low-dose aspirin required) without any GI risk factors (Lanza 2009).

Although the guidelines suggest the addition of a PPI or misoprostol for at-risk patients, it is estimated that 30% of patients are co-prescribed a PPI with an NSAID (Lanas 2009).

VIMOVO: A Potential Treatment Option

VIMOVO is a fixed-dose combination of EC-naproxen and immediate-release esomeprazole magnesium. VIMOVO is indicated to relieve the signs and symptoms of OA, RA, and AS in patients who are at risk of developing NSAID-associated gastric ulcers. VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months.

In two clinical studies, the therapeutic actions of VIMOVO after six months of treatment resulted in significant reduction in the incidence of gastric ulcers compared to EC-naproxen. In one study the cumulative incidence of gastric ulcers was 4.1% in patients receiving VIMOVO versus 23.1% in patients receiving EC-naproxen alone. In the second study, the cumulative incidence of gastric ulcers was 7.1% in patients receiving VIMOVO versus 24.3% in patients receiving EC-naproxen alone. Approximately a quarter of the patients in the clinical studies for VIMOVO were taking concurrent low-dose aspirin (≤325 mg daily). The results for this subgroup analysis of patients who used aspirin were consistent with the overall findings of the study.

The proportion of patients discontinuing treatment due to any upper GI adverse events (including duodenal ulcers) with VIMOVO was 4% compared to 12% for patients taking EC-naproxen.

The most common adverse reactions with VIMOVO in clinical trials (>5%): erosive gastric gastritis, diarrhea, gastric ulcer, upper abdominal pain, nausea.

VIMOVO is available in two dose strengths — 500 mg naproxen/20 mg esomeprazole magnesium tablets and 375 mg naproxen/20 mg esomeprazole magnesium tablets. The lowest effective dose for the shortest duration is recommended based on the individual patient treatment goals (VIMOVO™ Prescribing Information 2010).

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. VIMOVO can be administered with low-dose aspirin (≤325 mg/day) therapy. The concurrent use of aspirin and VIMOVO may increase the risk of serious adverse events. As with all NSAIDs, concurrent administration of naproxen and aspirin is not generally recommended because of the potential of increased adverse events.

Indications

VIMOVO is indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers. VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months.

Important Safety Information About VIMOVO

Cardiovascular Risk

  • Naproxen, a component of VIMOVO, may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

  • VIMOVO is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk

  • NSAIDs, including naproxen, a component of VIMOVO, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events.

VIMOVO is contraindicated in patients with known hypersensitivity to any component of VIMOVO or substituted benzimidazoles; in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; in patients during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery; or in patients in the late stages of pregnancy. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Treatment should be withdrawn when active and clinically significant bleeding from any source occurs.

As with all NSAIDs, VIMOVO can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Blood pressure should be monitored closely. NSAIDs, including VIMOVO, may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists, beta-blockers, and in some patients can reduce the natriuretic effect of furosemide and thiazides.

Fluid retention and edema have been observed in some patients taking NSAIDs, including VIMOVO. NSAIDs should be used with caution in patients with fluid retention or heart failure.

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. VIMOVO can be administered with low-dose aspirin (≤325 mg/day) therapy. The concurrent use of aspirin and VIMOVO may increase the risk of serious adverse events. As with all NSAIDs, concurrent administration of naproxen and aspirin is not generally recommended because of the potential of increased adverse events.

NSAIDs, including VIMOVO, can cause serious GI adverse events, which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. VIMOVO should be used with caution in these patients.

Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding. Although these studies focused on upper gastrointestinal bleeding, bleeding at other sites cannot be ruled out.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

Symptomatic response to esomeprazole, a component of VIMOVO, does not preclude the presence of gastric malignancy.

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which VIMOVO contains an enantiomer.

Anaphylactoid reactions may occur in patients without known prior exposure to either component of VIMOVO. NSAIDs should not be given to patients with aspirin triad.

Serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal and can occur without warning. Discontinue VIMOVO at first appearance of skin rash or any other sign of hypersensitivity.

In late pregnancy, as with other NSAIDS, VIMOVO should be avoided because it may cause premature closure of the ductus arteriosus.

VIMOVO is not recommended in patients with moderate or severe renal insufficiency. In addition, NSAIDs may cause renal toxicity.

VIMOVO is not recommended in patients with severe hepatic insufficiency. Consider dose reduction in mild/moderate hepatic insufficiency. If abnormal liver enzymes persist or worsen discontinue use immediately.

Several studies and literature reports indicate that long-term proton pump inhibitor (PPI) therapy is associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.

Esomeprazole, a component of VIMOVO, inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, iron salts, and digoxin).

Concomitant use of VIMOVO and warfarin may result in increased risk of bleeding complications. Monitor for increases in INR and prothrombin time.

The most commonly observed adverse events in clinical trials (experienced by >5% patients in the VIMOVO group) were erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, and nausea.

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