Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Severe Cutaneous Adverse Reactions
New
subsection added
Severe
cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic
symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have
been reported in association with the use of PPIs [see Adverse Reactions (6.2)].
![]()
Discontinue NEXIUM I.V. at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
5.8 Hypomagnesemia and Mineral Metabolism
Additions
and/or revisions underlined
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.
Hypomagnesemia
may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying
hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia
required magnesium replacement and discontinuation of the PPI.
…
Consider
monitoring magnesium and calcium levels prior to initiation of NEXIUM I.V. and
periodically while on treatment in patients with a preexisting risk of
hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or
calcium, as necessary. If hypocalcemia is refractory to treatment, consider
discontinuing the PPI.
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
6.2 Postmarketing
Experience
Additions
underlined
…
Skin and
Subcutaneous Tissue Disorders: alopecia, erythema multiforme,
hyperhidrosis, photosensitivity, Stevens- Johnson syndrome, toxic epidermal
necrolysis (TEN, some fatal), drug reaction with eosinophilia and systemic
symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP),
cutaneous lupus erythematosus.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
underlined
Adverse
Reactions
Advise
patients to report to their healthcare provider if they experience any signs or
symptoms consistent with:
…
…
Approved Drug Label (PDF)
4
Contraindications
Additions and/or revesions underlined
NEXIUM
I.V. is contraindicated in patients with known hypersensitivity to substituted
benzimidazoles or to any component of the formulation. Hypersensitivity
reactions may include anaphylaxis, anaphylactic shock, angioedema,
bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2), Adverse
Reactions (6.2)].
…
5
Warnings and Precautions
5.2 Acute Tubulointerstitial Nephritis
Additions and/or revisions underlined
Acute
tubulointerstitial nephritis (TIN) has been observed in patients
taking PPIs and may occur at any point during PPI therapy. Patients may
present with varying signs and symptoms from symptomatic hypersensitivity reactions
to non- specific symptoms of decreased renal function (e.g., malaise, nausea,
anorexia). In reported case series, some patients were diagnosed on biopsy and
in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).
Discontinue NEXIUM I.V. and evaluate patients with suspected acute TIN [see Contraindications (4)].
6
Adverse Reactions
Additions and/or
revisions underlined
The
following serious adverse reactions are described below and elsewhere in
labeling:
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined
Adverse
Reactions
Advise
patients to report to their healthcare provider if they experience any signs or
symptoms consistent with:
…
…
Approved Drug Label (PDF)
4
Contraindications
(Additions
and/or revisions are underlined)
NEXIUM I.V. is contraindicated in patients with
known hypersensitivity to substituted benzimidazoles or to any component of the
formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic
shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria.
Proton pump inhibitors (PPIs), including
NEXIUM I.V., are contraindicated in patients receiving rilpivirine- containing
products.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
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.
Symptomatic GERD and EE
Adults
The safety of NEXIUM
I.V. is based on results from clinical trials conducted in four different
populations including healthy subjects (n=204) and patients with bleeding
gastric or duodenal ulcers (n=375).
The data described below
reflect exposure to NEXIUM I.V. in 359 patients in actively-controlled trials: symptomatic
GERD with or without a history of EE (n=199) and patients with EE (n=160).
The population was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black,
3% Asian, and 28% other race. Most patients received doses of
either 20 or 40 mg either as an infusion or an injection. Adverse reactions occurring in at least
1% of patients are listed below in Table 3:
Intravenous treatment with NEXIUM I.V. 20 and 40
mg-administered as an injection or as an infusion was found to have a safety
profile similar to that of oral esomeprazole.
Pediatrics
A randomized,
open-label, multi-national study to evaluate the pharmacokinetics of repeated
intravenous doses of once daily NEXIUM I.V. in pediatric patients 1
month to 17 years old, inclusive was performed. The safety results are
consistent with the known safety profile of esomeprazole and no unexpected
safety signals were identified.
Risk Reduction of Rebleeding
of Gastric or Duodenal Ulcers in Adults
The data described in
Table 4 below reflect exposure to NEXIUM I.V. in 375 patients who
presented with endoscopically confirmed gastric or duodenal ulcer bleeding in
a placebo-controlled trial. The population was 18 to 98 years old; 68% Male,
87% Caucasian, 1% Black, 7% Asian, and 4% other race. Following endoscopic hemostasis, patients
received either placebo or 80 mg NEXIUM I.V. as an intravenous
infusion over 30 minutes followed by a continuous infusion of 8 mg/hour for a
total treatment duration of 72 hours. After the initial 72-hour period, all
patients received an oral PPI for 27
days.
With the
exception of injection site reactions described above, intravenous treatment
with NEXIUM I.V. administered as
an injection or as an infusion was found to have a safety profile similar to
that of oral esomeprazole.
6.2 Postmarketing Experience
(Additions and/or revisions are
underlined)
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.
Blood and Lymphatic System Disorders: agranulocytosis,
pancytopenia;
Eye Disorders: blurred vision;
Gastrointestinal
Disorders: pancreatitis; stomatitis; microscopic colitis; fundic gland
polyps;
Adverse
reactions associated with omeprazole may also be expected to
occur with NEXIUM I.V. See the full prescribing information for oral
omeprazole for complete safety information.
7
Drug Interactions
(Extensive
changes; please refer to labeling)
8
Use in Specific Populations
8.4 Pediatric Use
(Additions
and/or revisions are underlined)
The safety and effectiveness of
NEXIUM I.V. have been established in pediatric patients 1 month to 17 years of
age for the short-term treatment of GERD with EE, as an alternative
to oral therapy when oral NEXIUM is not possible or appropriate.
Use of NEXIUM
I.V. in this age group is based on extrapolation of adult efficacy to children
and the selection of dose based on exposure-matching of pediatrics to
adults supported by the following evidence: a) results observed from
a pharmacokinetic (PK) study on NEXIUM I.V. for Injection 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 from adequate and well- controlled studies that supported the
approval of NEXIUM I.V. in adults.
The safety and
effectiveness of NEXIUM I.V. have not been established in patients less than
1 month of age for the treatment of GERD with EE or for risk reduction of
rebleeding of gastric or duodenal ulcer following therapeutic endoscopy.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
In a clinical
trial of patients with bleeding gastric or duodenal ulcers, 52% of 375
patients randomized to NEXIUM I.V. were 65 years of age and over.
No overall differences in safety and efficacy were observed between the elderly
and younger individuals, and other reported clinical experience with NEXIUM
I.V. and oral esomeprazole has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
8.6 Hepatic Impairment
(Additions and/or revisions are underlined)
GERD with EE
Exposure to
esomeprazole was increased substantially in patients with severe hepatic
impairment (Child-Pugh Class C) but not in patients with mild to moderate
hepatic impairment (Child-Pugh Classes A and B) compared to
patients with normal liver function.
For adult
patients, no dosage adjustment is necessary for mild to moderate hepatic
impairment. For patients with severe hepatic impairment the maximum
recommended dosage is 20 mg once daily.
Risk Reduction of Rebleeding of Gastric
or Duodenal Ulcers following Therapeutic Endoscopy
There are no
pharmacokinetic data available for NEXIUM I.V. administered as continuous
intravenous administration in patients with hepatic impairment. Exposure to
intravenous omeprazole, of which esomeprazole is an enantiomer, increased in
patients with all degrees of hepatic impairment compared to subjects with
normal liver function.
For adult patients, no dosage adjustment of the initial NEXIUM
I.V. 80 mg loading dose is necessary for patients with any degree
of hepatic impairment. Reduce the rate of the continuous infusion to 6 mg/hour
for patients with mild to moderate liver impairment (Child-Pugh Classes A
and B) and to 4 mg/hour for patients with severe hepatic
impairment (Child-Pugh Class C).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
Adverse Reactions
Advise patients to report to
their healthcare provider if they experience any signs or symptoms consistent
with:
- Hypersensitivity Reactions
Acute Interstitial Nephritis
Clostridium
difficile-Associated Diarrhea
Bone Fracture
Cutaneous and Systemic Lupus Erythematosus
Hypomagnesemia
Drug Interactions
Advise patients to report to
their healthcare provider before they start treatment with any
of the following:
Administration
Approved Drug Label (PDF)
5
Warnings and Precautions
5.11 Fundic Gland Polyps
(Newly added subsection)
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.
6
Adverse Reactions
6 ADVERSE REACTIONS
(Additions and/or revisions are
underlined)
The following serious adverse reactions are
described below and elsewhere in labeling:
….
Hypomagnesemia
Fundic Gland Polyps
6.2 Postmarketing Experience
(Additions and/or revisions are
underlined)
…
Disorders: pancreatitis;
stomatitis; microscopic colitis;
fundic gland polyps; Hepatobiliary Disorders:
hepatic failure, hepatitis with or
without jaundice
…
Approved Drug Label (PDF)
5
Warnings and Precautions
(Additions and/or revisions are underlined in
subsection title)
5.8 Interaction with St. John’s Wort or Rifampin
5.9 Interactions with Diagnostic Investigations
for Neuroendocrine Tumors
5.10 Interaction with Methotrexate
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR)
Conversion; Additions and/or revisions are underlined)
Risk Summary
…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).
…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.
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%,
respectively.
Data
Human Data
…A small prospective observational cohort
study followed 113 women exposed to omeprazole during pregnancy (89% with first
trimester exposures)…
Animal Data
Omeprazole
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
embryo- lethality, 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.
Esomeprazole
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 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.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule
Conversion; Additions and/or revisions are underlined)
Risk Summary
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
maternal condition.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 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
who have suboptimal response or an early symptomatic relapse after
completing treatment with a PPI. In older patients also consider an endoscopy.
(Additions and/or revisions underlined)
5.5 Cutaneous and Systemic Lupus Erythematosus
Cutaneous lupus erythematosus (CLE) and systemic lupus
erythematosus (SLE) have been reported in patients taking PPIs, including NEXIUM . 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, 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.
6
Adverse Reactions
The
following serious adverse reactions are described below and elsewhere in
labeling:
- Acute
Interstitial Nephritis
- Clostridium
difficile-Associated Diarrhea
- Bone
Fracture
- Cutaneous
and Systemic Lupus Erythematosus
- Hypomagnesemia
6.2 Postmarketing Experience
The
following adverse reactions have been identified during post-approval use of NEXIUM:
Immune
System: anaphylactic reaction/shock; systemic lupus erythematosus
Skin and
Subcutaneous Tissue: alopecia,
erythema multiforme, hyperhidrosis, photosensitivity, Stevens- Johnson syndrome, toxic epidermal necrolysis
(some fatal), cutaneous lupus erythematosus.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Adverse
Reactions
- Advise
patients to report to their healthcare provider if they experience any
signs or symptoms consistent with:
Hypersensitivity Reactions
Acute Interstitial Nephritis
Clostridium
difficile-Associated Diarrhea
Bone Fracture
Cutaneous and Systemic Lupus Erythematosus
Hypomagnesemia
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