esomeprazole/naproxen (Rx)

>10%

Gastric erosion (19%); compared with 38% for equal naproxen dose without PPI

Dyspepsia (18%); compared with 27% for equal naproxen dose without PPI

Gastritis (17%)

1-10%

Diarrhea (6%)

Abdominal pain (6%)

Nausea (5%)

Hiatal hernia (4%)

Abdominal distension (4%)

Flatulence (4%)

Esophagitis (4%)

Constipation (3%)

Headache (3%)

Dysgeusia (2%)

Erosive duodenitis (2%)

Hemorrhagic gastritis (1%)

<1%

GERD

Duodenal ulcer

Erosive esophagitis

Postmarketing reports

Gait disturbance

Abdominal distension

Gastroesophageal reflux

Hematochezia

Contusion

Fall

Joint swelling

Muscle spasms

Renal tubular necrosis

Naproxen

• Body as a Whole: Angioneurotic edema, menstrual disorders
• Cardiovascular: Congestive heart failure, vasculitis, pulmonary edema
• Gastrointestinal: Inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, and obstruction of the upper or lower gastrointestinal tract, esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease)
• Hepatobiliary: Hepatitis (some cases have been fatal)
• Hemic and Lymphatic: Eosinophilia, hemolytic anemia, aplastic anemia
• Metabolic and Nutritional: Hyperglycemia, hypoglycemia
• Nervous System: Depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions
• Respiratory: Eosinophilic pneumonitis
• Dermatologic: Alopecia, urticaria, 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.
• 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

• Blood and Lymphatic: Agranulocytosis
• Eye: Blurred vision
• Gastrointestinal: Pancreatitis, microscopic colitis, fundic gland polyps
• Hepatobiliary: Hepatic failure, hepatitis with or without jaundice
• Immune System: Anaphylactic reaction/shock
• Infections and Infestations: GI candidiasis, Clostridium difficile associated diarrhea
• Metabolism and Nutritional Disorders: Hypomagnesemia, with or without hypocalcemia and/or hypokalemia
• Musculoskeletal and Connective Tissue: Muscular weakness, myalgia, bone fracture
• Nervous System: Hepatic encephalopathy
• Psychiatric: Aggression, agitation, hallucination
• Renal and Urinary: Interstitial nephritis
• Reproductive System and Breast: Gynecomastia
• Respiratory, Thoracic, and Mediastinal: Bronchospasm
• Skin and Subcutaneous Tissue: Alopecia, erythema multiforme, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal)
• Nutrition: Cyanocobalamin (vitamin B-12) deficiency

Contraindications

Hypersensitivity, including angioedema and anaphylactic reaction/shock has been reported with esomeprazole

Asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs

NSAIDs are contraindicated in late stage pregnancy (risk for closure of ductus arteriosus)

NSAIDs are contraindicated for perioperative pain in setting of CABG surgery

Perioperative pain in the setting of coronary artery bypass graft surgery

Concomitant administration with rilpivirine-containing products

Cautions

NSAIDs increase risk for thrombotic events (eg, MI, stroke); consistent evidence does not exist that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events

NSAIDs increase risk for hypertension (or worsening hypertension), CHF, and edema

NSAIDs increase risk of GI ulceration, bleeding, and perforation

Caution with history of inflammatory bowel disease or GI bleeding

Long-term NSAID use may cause renal papillary necrosis or other renal injury; patients at greatest risk include elderly individuals, those with impaired renal function, hypovolemia, heart failure, liver dysfunction, or salt depletion, and those taking diuretics, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers

Caution with pre-existing asthma

Inhibits platelet aggregation

PPIs may increase risk of osteoporosis-related fractures

Relief of symptoms does not eliminate the possibility of a gastric malignancy; consider additional follow-up and diagnostic testing in adult patients who have suboptimal response or early symptomatic relapse after completing treatment with a PPI

Hypomagnesemia may occur with prolonged use (ie, >1 year); adverse effects may result and include tetany, arrhythmias, or seizures; in 25% of cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued; consider monitoring magnesium levels prior to initiation of PPI treatment and periodically

PPIs possibly associated with increased incidence of Clostridium difficile-associated diarrhea (CDAD); consider diagnosis of CDAD for patients taking PPIs with diarrhea that does not improve

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) reported with PPIs; avoid using for longer than medically indicated; discontinue if signs or symptoms consistent with CLE or SLE are observed and refer patient to specialist; most patients improve with discontinuation of PPI alone in 4-12 weeks; serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations

PPIs decreased gastric acidity increases serum chromogranin A (CgA) levels and may cause false-positive diagnostic results for neuroendocrine tumors; temporarily discontinue PPIs before assessing CgA levels

Acute interstitial nephritis reported in patients taking PPIs; may occur at any point during PPI therapy and is generally attributed to idiopathic hypersensitivity reaction; discontinue therapy if acute interstitial nephritis develops

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo-or achlorhydria; rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy reported

Patients with advanced renal disease should be adequately hydrated

If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, discontinue treatment and monitor patient

May elevate and/or prolong serum concentrations of methotrexate and/or its metabolite when administered oncomitantly with PPIs, possibly leading to toxicity; consider a temporary withdrawal of PPI therapy therapy with high dose methotrexate administration

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including, may delay or prevent rupture of ovarian follicles that may lead to reversible infertility in some women; consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing investigation of infertility

PPI therapy is associated with increased risk of fundic gland polyp; risk increases with long-term use >1 year; patient may be asymptomatic; problem usually identified incidentally on endoscopy; use shortest duration of therapy appropriate to condition being treated

Pregnancy

Use of NSAIDs during third trimester of pregnancy increases risk of premature closure of fetal ductus arteriosus; avoid use of NSAIDs in pregnant women starting at 30 weeks of gestation (third trimester); there are no adequate and well-controlled studies on this therapy in pregnant women

There are no studies on effects of therapy during labor or delivery; in animal studies, NSAIDs, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase incidence of stillbirth

Lactation

Limited data from published literature report that naproxen anion has been found in milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma; esomeprazole is the S-isomer of omeprazole and limited data from published literature suggest omeprazole may be present in human milk; there is no information on effects of naproxen or omeprazole on breastfed infant or on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

Lactation: Naproxen is distributed in breast milk, not recommended

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Naproxen: NSAID that inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis; has antipyretic and analgesic effects

Esomeprazole: S-isomer of omeprazole, a proton pump inhibitor; inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system at secretory surface of gastric parietal cells

Naproxen

Half-Life: 13-15 hr

Bioavailability: 95%

Duration: 4-7 hr

Onset: 1 hr

Distribution: 0.16 L/kg

Peak Serum Time: 1.5-3 hr; high fat meal prolongs Tmax by 10 hr

Peak Plasma Concentration: 62-96 mcg/mL Vd: 0.16 L/kg

Protein Bound: >99% albumin

Metabolism: hepatic via CYP2C9, CYP1A2; also undergoes hepatic conjugation

Clearance: 0.13 L/min/kg

Excretion: feces < 3%, urine 95%

Esomeprazole

Half-Life: 1.2-1.5 hr

Bioavailability: 90%, food decreases AUC by 33-53%

Duration: 17 hr gastric acid inhibition at steady state

Onset: 1-2 hr

Peak Plasma Time: 1-1.6 hr

Vd: 16 L

Protein Bound: 97%

Clearance: 9-16 L/hr

Excretion: Feces 20%, urine 80%

Metabolism

• Extensively by hepatic P450 enzyme: major metabolic pathway is via CYP2C19, the rest is via CYP3A4
• Slow metabolizers (3% of Caucasians and African-Americans) are deficient in CPY2C19 enzyme system, plasma concentration can be higher than those with the enzyme present
• CYP2C19 inhibitor

Oral Administration

Tablet consists of immediate-release esomeprazole layer and enteric-coated naproxen core

Swallow whole; do not chew, crush, dissolve, or split