Renal Impairment

Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance less than 30 mL/min) [see Warnings and Precautions (5.6), Use in Specific Populations (8.7)].

Hepatic Impairment

Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose reduction based on the naproxen component of naproxen and esomeprazole magnesium delayed-release tablets.

Naproxen and esomeprazole magnesium delayed-release tablets should be avoided in patients with severe hepatic impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.6)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

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. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100-person years in NSAID-treated patients compared to 12 per 100-person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years after follow-up.

Avoid the use of naproxen and esomeprazole magnesium delayed-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If naproxen and esomeprazole magnesium delayed-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events are in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated Patients

•

Use the lowest effective dosage for the shortest possible duration.

•

Avoid administration of more than one NSAID at a time.

•

Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.

•

Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

•

If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue naproxen and esomeprazole magnesium delayed-release tablets until a serious GI adverse event is ruled out.

•

In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)].

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.

Renal Toxicity

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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of naproxen and esomeprazole magnesium delayed-release tablets in patients with advanced renal disease. The renal effects of naproxen and esomeprazole magnesium delayed-release tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating naproxen and esomeprazole magnesium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of naproxen and esomeprazole magnesium delayed-release tablets [see Drug Interactions (7)]. Avoid the use of naproxen and esomeprazole magnesium delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If naproxen and esomeprazole magnesium delayed-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit naproxen and esomeprazole magnesium delayed-release tablet use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if naproxen and esomeprazole magnesium delayed-release tablet treatment is needed in a pregnant woman. Discontinue naproxen and esomeprazole magnesium delayed-release tablets if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

Clinical Trials Experience with Naproxen and Esomeprazole Magnesium Delayed-Release Tablets

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 naproxen and esomeprazole magnesium delayed-release tablets.

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

The table below lists all adverse reactions, regardless of causality, occurring in > 2% of patients receiving naproxen and esomeprazole magnesium delayed-release tablets and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than control 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%).

In Study 1 and Study 2, patients taking naproxen and esomeprazole magnesium delayed-release tablets had fewer premature discontinuations due to adverse reactions compared to patients taking enteric-coated naproxen alone (7.9% vs 12.5% respectively). The most common reasons for discontinuations due to adverse events in the naproxen and esomeprazole magnesium delayed-release tablets 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 enteric-coated 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 gastrointestinal adverse events (including duodenal ulcers) in patients treated with naproxen and esomeprazole magnesium delayed-release tablets was 4% compared to 12% for patients taking enteric-coated naproxen.

The table below lists all adverse reactions, regardless of causality, occurring in > 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than placebo from 2 clinical studies conducted in patients with osteoarthritis of the knee (Study 3 and Study 4).

The percentage of subjects who withdrew from the naproxen and esomeprazole magnesium delayed-release tablets 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 naproxen and esomeprazole magnesium delayed-release tablets was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of naproxen and esomeprazole magnesium delayed-release tablets 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.

Clinical Trials Experience with Naproxen and Other NSAIDs

In patients taking naproxen in clinical trials, the most frequent reported adverse experiences in approximately 1% to 10% of patients are:

Gastrointestinal: heartburn, nausea, dyspepsia, stomatitis

Central Nervous System: drowsiness, lightheadedness, vertigo

Dermatologic: pruritus, skin eruptions, ecchymoses, sweating, purpura

Special Senses: tinnitus, visual disturbances, hearing disturbances

Cardiovascular: palpitations

General: dyspnea, thirst

In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients:

Gastrointestinal: gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting

General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes

The following are additional adverse experiences reported in < 1% of patients taking naproxen during clinical trials:

Gastrointestinal: pancreatitis

Hepatobiliary: jaundice

Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis

Nervous System: inability to concentrate

Dermatologic: skin rashes

In patients taking NSAIDs, the following adverse experiences have also been reported in < 1% of patients:

Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death

Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction

Gastrointestinal: dry mouth, glossitis, eructation

Hepatobiliary: hepatitis, liver failure

Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremor, coma, hallucinations

Respiratory: asthma, respiratory depression, pneumonia

Dermatologic: exfoliative dermatitis

Special Senses: blurred vision, conjunctivitis

Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria

Clinical Trials Experience with Esomeprazole Magnesium

Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence of < 1% are listed below by body system:

Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, malaise, pain, rigors

Cardiovascular: flushing, hypertension, tachycardia

Endocrine: goiter

Gastrointestinal: dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting

Hearing: earache, tinnitus

Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia

Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased

Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B-12 deficiency, weight increase, weight decrease

Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica

Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect

Reproductive: dysmenorrhea, menstrual disorder, vaginitis

Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis

Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria

Special Senses: otitis media, parosmia, taste loss

Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria

Visual: conjunctivitis, vision abnormal

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, were reported in ≤ 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone.

Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.

Naproxen and Esomeprazole Magnesium Delayed-Release Tablets

Body as a Whole: gait disturbance

Gastrointestinal: abdominal distension, abdominal pain, gastroesophageal reflux, hematochezia

Injury, Poisoning and Procedural Complications: contusion, fall

Musculoskeletal and Connective Tissue: joint swelling, muscle spasms

Urogenital: 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 erythematosus, 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 Magnesium

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, systemic lupus erythematosus

Infections and Infestations: GI candidiasis, Clostridium difficile-associated diarrhea

Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions (5.24)], hyponatremia

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, SJS, TEN (some fatal), DRESS, AGEP, cutaneous lupus erythematosus

Risk Summary

Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal and renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of naproxen and esomeprazole magnesium delayed-release tablet use between about 20 and 30 weeks of gestation and avoid naproxen and esomeprazole magnesium delayed-release tablet use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Clinical Considerations

Data

Risk Summary

Limited data from published literature report that 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 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 the effects of naproxen or omeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naproxen and esomeprazole magnesium delayed-release tablets and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Infertility

Juvenile Animal Data

In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)].

Interaction with Aspirin

In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%].

Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%] [see Drug Interactions (7)].

Antisecretory Activity

The effect of naproxen and esomeprazole magnesium delayed-release tablets on intragastric pH was determined in 25 healthy volunteers in one study. Three naproxen and esomeprazole magnesium delayed-release tablet combinations (naproxen 500 mg combined with either esomeprazole 10, 20, or 30 mg) were administered twice daily over 9 days. The results are shown in the following table:

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 two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.

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 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 or 40 mg for 2 to 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, in hospitalized patients, possibly also Clostridium difficile.

Absorption

Esomeprazole

Following administration of naproxen and esomeprazole magnesium delayed-release tablets 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 naproxen and esomeprazole magnesium delayed-release tablets.

Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of naproxen and esomeprazole magnesium delayed-release tablets 500 mg/20 mg.

Figure 1: Mean Plasma Concentrations of Naproxen and Esomeprazole Following Single Dose Administration of Naproxen and Esomeprazole Magnesium Delayed-Release Tablets (500 mg/20 mg)

Distribution

Elimination

Specific Populations

Drug Interaction Studies

Carcinogenesis

Mutagenesis

Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

Impairment of Fertility

The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 33.6 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

Studies to evaluate the impact of naproxen on male or female fertility have not been completed.

Naproxen

Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the maximum recommended human dose), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the maximum recommended human dose), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the maximum recommended human dose) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response.

Esomeprazole – Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8.1)].

Esomeprazole – Juvenile Animal Data

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.