Included as part of the PRECAUTIONS section.
Presence Of Gastric Malignancy
In adults, symptomatic response to therapy with NEXIUM
I.V. does not preclude the presence of gastric malignancy. Consider additional
follow-up and diagnostic testing in adults patients who have suboptimal
response or an early symptomatic relapse after completing treatment with a PPI.
In older patients also consider an endoscopy.
Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in
patients taking PPIs including NEXIUM I.V. Acute interstitial nephritis may
occur at any point during PPI therapy and is generally attributed to an
idiopathic hypersensitivity reaction. Discontinue NEXIUM I.V. if acute
interstitial nephritis develops [see CONTRAINDICATIONS].
Clostridium Difficile-Associated Diarrhea
Published observational studies suggest that PPI therapy
like NEXIUM may be associated with an increased risk of Clostridium
difficile-associated diarrhea, especially in hospitalized patients. This
diagnosis should be considered for diarrhea that does not improve [see
Patients should use the lowest dose and shortest duration
of PPI therapy appropriate to the condition being treated.
Several published observational studies suggest that
proton pump inhibitor (PPI) therapy may be associated with an increased risk
for osteoporosis-related fractures of the hip, wrist, or spine. The risk of
fracture was increased in patients who received high-dose, defined as multiple
daily doses, and long-term PPI therapy (a year or longer). Patients should use the
lowest 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 established treatment guidelines [see DOSAGE AND
ADMINISTRATION and ADVERSE REACTIONS].
Cutaneous And Systemic Lupus Erythematosus
Cutaneous lupus erythematosus (CLE) and systemic lupus
erythematosus (SLE) have been reported in patients taking PPIs, including
esomeprazole. These events have occurred as both new onset and an exacerbation
of existing autoimmune disease. The majority of PPI-induced lupus erythematosus
cases were CLE.
The most common form of CLE reported in patients treated
with PPIs was subacute CLE (SCLE) and occurred within weeks to years after
continuous drug therapy in patients ranging from infants to the elderly.
Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly
reported than CLE in patients receiving PPIs. PPI associated SLE is usually
milder than non-drug induced SLE. Onset of SLE typically occurred within days
to years after initiating treatment primarily in patients ranging from young
adults to the elderly. The majority of patients presented with rash; however,
arthralgia and cytopenia were also reported.
Avoid administration of PPIs for longer than medically
indicated. If signs or symptoms consistent with CLE or SLE are noted in
patients receiving NEXIUM I.V., discontinue the drug and refer the patient to
the appropriate specialist for evaluation. Most patients improve with
discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g.,
ANA) may be positive and elevated serological test results may take longer to
resolve than clinical manifestations.
Interaction With Clopidogrel
Avoid concomitant use of NEXIUM I.V. with clopidogrel.
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is
entirely due to an active metabolite. The metabolism of clopidogrel to its
active metabolite can be impaired by use with concomitant medications, such as
esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel
with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel.
When using NEXIUM I.V. consider alternative anti-platelet therapy [see DRUG
INTERACTIONS, CLINICAL PHARMACOLOGY].
Hypomagnesemia, symptomatic and asymptomatic, has been
reported rarely in patients treated with PPIs for at least three months, in
most cases after a year of therapy. Serious adverse events include tetany,
arrhythmias, and seizures. In most patients, treatment of hypomagnesemia
required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who
take PPIs with medications such as digoxin or drugs that may cause
hypomagnesemia (e.g., diuretics), health care professionals may consider
monitoring magnesium levels prior to initiation of PPI treatment and
periodically [see ADVERSE REACTIONS].
Interaction With St. John’s Wort Or Rifampin
Drugs which induce CYP2C19 or CYP3A4 (such as St. John's
Wort or rifampin) can substantially decrease esomeprazole concentrations [see
DRUG INTERACTIONS]. Avoid concomitant use of NEXIUM with St. John's Wort or
Interactions With Diagnostic Investigations For Neuroendocrine
Serum chromogranin A (CgA) levels increase secondary to
drug-induced decreases in gastric acidity. The increased CgA level 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. If serial tests are performed (e.g., for monitoring), the same
commercial laboratory should be used for testing, as reference ranges between
tests may vary [see CLINICAL PHARMACOLOGY].
Interaction With Methotrexate
Literature suggests that concomitant use of PPIs with
methotrexate (primarily at high dose; see methotrexate prescribing information)
may elevate and prolong serum levels of methotrexate and/or its metabolite,
possibly leading to methotrexate toxicities. In high-dose methotrexate
administration, a temporary withdrawal of the PPI may be considered in some patients
[see DRUG INTERACTIONS].
Fundic Gland Polyps
PPI use is associated with an increased risk of fundic
gland polyps that increases with long-term use, especially beyond one year.
Most PPI users who developed fundic gland polyps were asymptomatic and fundic
gland polyps were identified incidentally on endoscopy. Use the shortest
duration of PPI therapy appropriate to the condition being treated.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The carcinogenic potential of esomeprazole was assessed
using omeprazole studies. In two 24-month oral carcinogenicity studies in rats,
omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0, and 140.8 mg/kg/day (about
0.4 to 34 times the human dose of 40 mg/day expressed on a body surface area
basis) produced gastric ECL cell carcinoids in a dose-related manner in both
male and female rats; the incidence of this effect was markedly higher in
female rats, which had higher blood levels of omeprazole. Gastric carcinoids
seldom occur in the untreated rat. In addition, ECL cell hyperplasia was
present in all treated groups of both sexes. In one of these studies, female
rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human
dose of 40 mg/day on a body surface area basis) for 1 year, then followed for
an additional year without the drug. No carcinoids were seen in these rats. An
increased incidence of treatment-related ECL cell hyperplasia was observed at
the end of 1 year (94% treated vs 10% controls). By the second year the
difference between treated and control rats was much smaller (46% vs 26%) but
still showed more hyperplasia in the treated group. Gastric adenocarcinoma was
seen in one rat (2%). No similar tumor was seen in male or female rats treated
for 2 years. For this strain of rat no similar tumor has been noted
historically, but a finding involving only one tumor is difficult to interpret.
A 78-week oral mouse carcinogenicity study of omeprazole did not show increased
tumor occurrence, but the study was not conclusive.
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.
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 34 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.
Use In Specific Populations
There are no adequate and well-controlled studies with
NEXIUM in pregnant women. Esomeprazole is the s-isomer of omeprazole. Available
epidemiologic data fail to demonstrate an increased risk of major congenital
malformations or other adverse pregnancy outcomes with first trimester
omeprazole use. Reproduction studies in rats and rabbits resulted in dose-dependent
embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an
oral human dose of 40 mg (based on a body surface area for a 60 kg person).
Teratogenicity was not observed in animal reproduction
studies with administration of oral esomeprazole magnesium in rats and rabbits
with doses about 68 times and 42 times, respectively, an oral human dose of 40
mg (based on a body surface area basis for a 60 kg person). Changes in bone
morphology were observed in offspring of rats dosed through most of pregnancy
and lactation at doses equal to or greater than approximately 34 times an oral
human dose of 40 mg. When maternal administration was confined to gestation
only, there were no effects on bone physeal morphology in the offspring at any
age [see Data].
The estimated background risks of major birth defects and
miscarriage for the indicated population are unknown. All pregnancies have a
background risk of birth defect, loss or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
Esomeprazole is the S-isomer of omeprazole. Four
epidemiological studies compared the frequency of congenital abnormalities
among infants born to women who used omeprazole during pregnancy with the
frequency of abnormalities among infants of women exposed to H2 receptor
antagonists or other controls.
A population based retrospective cohort epidemiological
study from the Swedish Medical Birth Registry, covering approximately 99% of
pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the
first trimester with 39 of these exposed beyond first trimester, and 131
exposed after the first trimester) whose mothers used omeprazole during
pregnancy. The number of infants exposed in utero to omeprazole that had any
malformation, low birth weight, low Apgar score, or hospitalization was similar
to the number observed in this population. The number of infants born with
ventricular septal defects and the number of stillborn infants was slightly
higher in the omeprazole-exposed infants than the expected number in this
A population-based retrospective cohort study covering
all live births in Denmark from 1996 to 2009, reported on 1,800 live births
whose mothers used omeprazole during the first trimester of pregnancy and
837,317 live births whose mothers did not use any proton pump inhibitor. The
overall rate of birth defects in infants born to mothers with first trimester exposure
to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any
proton pump inhibitor during the first trimester.
A retrospective cohort study reported on 689 pregnant
women exposed to either H2-blockers or omeprazole in the first trimester (134
exposed to omeprazole) and 1,572 pregnant women unexposed to either during the
first trimester. The overall malformation rate in offspring born to mothers
with first trimester exposure to omeprazole, an H2-blocker, or were unexposed
was 3.6%, 5.5%, and 4.1% respectively.
A small prospective observational cohort study followed
113 women exposed to omeprazole during pregnancy (89% with first trimester
exposures). The reported rate of major congenital malformations was 4% in the
omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease
paired controls. Rates of spontaneous and elective abortions, preterm
deliveries, gestational age at delivery, and mean birth weight were similar
among the groups.
Several studies have reported no apparent adverse
short-term effects on the infant when single dose oral or intravenous omeprazole
was administered to over 200 pregnant women as premedication for cesarean
section under general anesthesia.
Reproductive studies conducted with omeprazole in rats at
oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a
body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34
times an oral human dose of 40 mg on a body surface area basis) during
organogenesis did not disclose any evidence for a teratogenic potential of
omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day
(about 3.4 to 34 times an oral human dose of 40 mg on a body surface area
basis) administered during organogenesis produced dose-related increases in
embryolethality, fetal resorptions, and pregnancy disruptions. In rats,
dose-related embryo/fetal toxicity and postnatal developmental toxicity were
observed in offspring resulting from parents treated with omeprazole at 13.8 to
138.0 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body
surface area basis), administered prior to mating through the lactation period.
No effects on embryo-fetal development were observed in
reproduction studies with esomeprazole magnesium 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) or in rabbits at oral doses up to 86 mg/kg/day (about 41 times the
human dose on a body surface area basis) administered during organogenesis.
A pre- and postnatal developmental toxicity study in rats
with additional endpoints to evaluate bone development was performed with
esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68
times an oral human dose of 40 mg on a body surface area basis). Neonatal/early
postnatal (birth to weaning) survival was decreased at doses equal to or
greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a
body surface area basis). Body weight and body weight gain were reduced and
neurobehavioral or general developmental delays in the immediate post-weaning timeframe
were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an
oral human dose of 40 mg on a body surface area basis). In addition, decreased
femur length, width and thickness of cortical bone, decreased thickness of the
tibial growth plate and minimal to mild bone marrow hypocellularity were noted
at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human
dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was
observed in offspring of rats treated with oral doses of esomeprazole magnesium
at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human
dose of 40 mg on a body surface area basis).
Effects on maternal bone were observed in pregnant and
lactating rats in a pre- and postnatal toxicity study when esomeprazole
magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to
68 times an oral human dose of 40 mg on a body surface area basis). When rats
were dosed from gestational day 7 through weaning on postnatal day 21, a
statistically significant decrease in maternal femur weight of up to 14% (as
compared to placebo treatment) was observed at doses equal to or greater than
138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area
A pre- and postnatal development study in rats with
esomeprazole strontium (using equimolar doses compared to esomeprazole
magnesium study) produced similar results in dams and pups as described above.
A follow up developmental toxicity study in rats with
further time points to evaluate pup bone development from postnatal day 2 to
adulthood was performed with esomeprazole magnesium at oral doses of 280
mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area
basis) where esomeprazole administration was from either gestational day 7 or
gestational day 16 until parturition. When maternal administration was confined
to gestation only, there were no effects on bone physeal morphology in the
offspring at any age.
Esomeprazole is the S-isomer of omeprazole and limited
data suggest that omeprazole may be present in human milk. There are no
clinical data on the effects of esomeprazole 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 NEXIUM and any potential
adverse effects on the breastfed infant from NEXIUM or from the underlying
The safety and effectiveness of NEXIUM I.V. for Injection
have been established in pediatric patients 1 month to 17 years of age for
short-term treatment of GERD with Erosive Esophagitis [see CLINICAL
PHARMACOLOGY]. However, effectiveness has not been established in patients
less than 1 month of age.
1 Month To 17 Years Of Age
Use of NEXIUM I.V. for Injection in pediatric patients 1
month to 17 years of age for short-term treatment of GERD with Erosive
Esophagitis is supported by: a) results observed from a pharmacokinetic (PK)
study on NEXIUM I.V. for Injection performed in pediatric patients, b)
predictions from a population PK model comparing I.V. PK data between adult and
pediatric patients, and c) relationship between exposure and pharmacodynamic
results obtained from adult I.V. and pediatric oral data and d) PK results
already included in the current approved labeling and from adequate and
wellcontrolled studies that supported the approval of NEXIUM I.V. for Injection
Neonates 0 To 1 Month Of Age
Following administration of NEXIUM I.V. in neonates the
geometric mean (range) for CL was 0.17 L/h/kg (0.04 L/h/kg- 0.32 L/h/kg).
The safety and effectiveness of NEXIUM I.V. in neonates
have not been established.
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].
Of the total number of patients who received oral NEXIUM
in clinical trials, 1,459 were 65 to 74 years of age and 354 patients were ≥
75 years of age.
No overall differences in safety and efficacy were
observed between the elderly and younger individuals, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
For adult patients with GERD, no dosage adjustment is
necessary in patients with mild to moderate hepatic insufficiency (Child-Pugh
Classes A and B). For patients with severe hepatic insufficiency (Child-Pugh
Class C) a dose of 20 mg once daily should not be exceeded [see DOSAGE AND
ADMINISTRATION, CLINICAL PHARMACOLOGY].
For adult patients with bleeding gastric or duodenal
ulcers and liver impairment, no dosage adjustment of the initial esomeprazole
80 mg infusion is necessary. For adult patients with mild to moderate liver
impairment (Child-Pugh Classes A and B), a maximum continuous infusion of
esomeprazole 6 mg/h should not be exceeded. For adult patients with severe
liver impairment (Child-Pugh Class C), a maximum continuous infusion of 4 mg/h
should not be exceeded [see DOSAGE AND ADMINISTRATION, CLINICAL