Included as part of the PRECAUTIONS section.
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, including myocardial
infarction (MI), and stroke, which can be fatal. Based on available data, it is
unclear that the risk for CV thrombotic events is similar for all NSAIDS. The
relative increase in serious CV thrombotic events over baseline conferred by
NSAID use appears to be similar in those with and without known CV disease or
risk factors for CV disease. However, patients with known CV disease or risk
factors had a higher absolute incidence of excess serious CV thrombotic events,
due to their increased baseline rate. Some observational studies found that
this increased risk of serious CV thrombotic events began as early as the first
weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in
NSAID-treated patients, use the lowest effective dose for the shortest duration
possible. Physicians and patients should remain alert for the development of
such events, throughout the entire treatment course, even in the absence of
previous CV symptoms. Patients should be informed about the 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. The concurrent use of aspirin and an NSAID, such as naproxen,
increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration, and Perforation].
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].
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 VIMOVO in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If VIMOVO is used in patients with a recent MI, monitor
patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including naproxen, can cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused
by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and
in about 2% to 4% of patients treated for one year. However, even short-term
NSAID therapy is not without risk.
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
- Use the lowest effective dosage for the shortest possible
- 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 as patients, as
well as those with active GI bleeding, consider alternate therapies other than
- 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 VIMOVO 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].
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.
Elevations of ALT or AST (three or more times the upper
limit of the normal [ULN]) have been reported in approximately 1% of
NSAID-treated patients in clinical trials. In addition, rare, and sometimes
fatal, cases of severe hepatic injury, including jaundice and fatal fulminant
hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may
occur in up to 15% of patients treated with NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs
and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIMOVO
immediately, and perform a clinical evaluation of the patient.
VIMOVO should be avoided in patients with severe hepatic
impairment [see DOSAGE AND ADMINISTRATION, Use In Specific
Populations, and CLINICAL PHARMACOLOGY].
NSAIDs, including VIMOVO, can lead to new onset of
hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events.
Patients taking angiotensin converting enzyme (ACE)
inhibitors, thiazides diuretics, or loop diuretics may have impaired response
to these therapies when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of
NSAID treatment and throughout the course of therapy.
Heart Failure And Edema
The Coxib and traditional NSAID Trialists' Collaboration
meta-analysis of randomized controlled trials demonstrated an approximately
two-fold increase in hospitalizations for heart failure in COX-2 selective
treated patients and nonselective NSAID-treated patients compared to
placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart
failure, and death.
Additionally, fluid retention and edema have been
observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV
effects of several therapeutic agents used to treat these medical conditions
(e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see
Avoid the use of VIMOVO in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If VIMOVO is used in patients with severe heart failure, monitor
patients for signs and symptoms of worsening heart failure.
Renal Toxicity And Hyperkalemia
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 VIMOVO in patients with advanced renal disease.
The renal effects of VIMOVO 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 VIMOVO. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of VIMOVO [see DRUG INTERACTIONS]. Avoid the use of VIMOVO in
patients with advanced renal disease unless the benefits are expected to
outweigh the risk of worsening renal failure. If VIMOVO is used in patients
with advanced renal disease, monitor patients for signs of worsening renal
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.
Naproxen has been associated with anaphylactic reactions
in patients with and without known hypersensitivity to naproxen and in patients
with aspirin-sensitive asthma [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive
asthma which may include chronic rhinosinusitis complicated by nasal polyps;
severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other
NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been
reported in such aspirin-sensitive patients, VIMOVO is contraindicated in
patients with this form of aspirin sensitivity [see CONTRAINDICATIONS].
When VIMOVO is used in patients with preexisting asthma (without known aspirin
sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including naproxen, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS),
and toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Inform patients about the signs and symptoms of
serious skin reactions, and to discontinue the use of VIMOVO at the first
appearance of skin rash or any other sign of hypersensitivity. VIMOVO is
contraindicated in patients with previous serious skin reactions to NSAIDs [see
Premature Closure Of Fetal Ductus Arteriosus
Naproxen may cause premature closure of the fetal ductus
arteriosus. Avoid use of NSAIDs, including VIMOVO, in pregnant women starting
at 30 weeks of gestation (third trimester) [see Use In Specific Populations].
Anemia has occurred in NSAID-treated patients. This may
be due to occult or gross blood loss, fluid retention, or an incompletely
described effect on erythropoiesis. If a patient treated with VIMOVO has any
signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including VIMOVO, may increase the risk of
bleeding events. Co-morbid conditions such as coagulation disorders or
concomitant use of warfarin and other anticoagulants, antiplatelet agents
(e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) may increase the risk. Monitor these
patients for signs of bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of VIMOVO in reducing
inflammation, and possibly fever, may diminish the utility of diagnostic signs
in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal
injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and chemistry profile
periodically [see Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity and Renal Toxicity and Hyperkalemia].
Patients with initial hemoglobin values of 10 g or less
who are to receive long-term therapy should have hemoglobin values determined
When active and clinically significant bleeding from any
source occurs in patients receiving VIMOVO, the treatment should be withdrawn.
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
non-aspirin NSAID should be avoided due to the potential for increased risk of
Presence Of Gastric Malignancy
In adults, response to gastric symptoms with VIMOVO does
not preclude the presence of gastric malignancy. Consider additional
gastrointestinal follow-up and diagnostic testing in adult patients who
experience gastric symptoms during treatment with VIMOVO or have a symptomatic
relapse after completing treatment. In older patients, also consider an
Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in
patients taking PPIs including VIMOVO. Acute interstitial nephritis may occur
at any point during PPI therapy and is generally attributed to an idiopathic
hypersensitivity reaction. Discontinue VIMOVO if acute interstitial nephritis
develops [see CONTRAINDICATIONS].
Clostridium Difficile-Associated Diarrhea
Published observational studies suggest that proton pump
inhibitor (PPI) therapy like VIMOVO 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 ADVERSE REACTIONS].
Patients should use the lowest dose and shortest duration
of PPI therapy appropriate to the condition being treated [see DOSAGE AND
Several published observational studies suggest that 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 the established treatment guidelines [see DOSAGE AND ADMINISTRATION and
VIMOVO (a combination PPI/NSAID) is approved for use
twice a day and does not allow for administration of a lower daily dose of the
PPI [see DOSAGE AND ADMINISTRATION].
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 erythematous
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 inpatients ranging from infants to the elderly.
Generally, histological findings were observed without organ involvement.
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
Avoid administration of PPIs for longer than medically
indicated. If signs or symptoms consistent with CLE or SLE are noted in
patients receiving VIMOVO, discontinue 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
Interaction With Clopidogrel
Avoid concomitant use of esomeprazole 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 esomeprazole, a component of VIMOVO, consider alternative
anti-platelet therapy [see DRUG INTERACTIONS and CLINICAL
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 B-12) caused by hypo-or achlorhydria.
Rare reports of cyanocobalamin deficiency occurring with acid-suppressing
therapy have been reported in the literature. This diagnosis should be
considered if clinical symptoms consistent with cyanocobalamin deficiency are
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].
Concomitant Use Of St. John’sWort Or Rifampin With VIMOVO
Drugs that induce CYP2C19 or CYP3A4 (such as St.
John'sWort or rifampin) can substantially decrease esomeprazole concentrations.
Avoid concomitant use of VIMOVO with St. John's Wort or rifampin [see DRUG
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.
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 DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Concomitant Use Of VIMOVO 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.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide).
Inform patients, families, or
caregivers of the following before initiating therapy with VIMOVO and
periodically during the course of ongoing therapy.
Advise patients to be alert for
the symptoms of cardiovascular thrombotic events, including chest pain,
shortness of breath, weakness, or slurring of speech, and to report any of
these symptoms to their health care provider immediately [see WARNINGS
Ulceration, And Perforation
Advise patients to report
symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia,
melena, and hematemesis to their health care provider. In the setting of
concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of
the increased risk for and the signs and symptoms of GI bleeding [see WARNINGS
Inform patients of the warning
signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,
pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, instruct patients to stop VIMOVO and seek immediate medical
therapy [see WARNINGS AND PRECAUTIONS].
Heart Failure And Edema
Advise patients to be alert for
the symptoms of congestive heart failure including shortness of breath,
unexplained weight gain, or edema and to contact their health care provider if
such symptoms occur [see WARNINGS AND PRECAUTIONS].
Inform patients of the signs of an anaphylactic reaction
(e.g., difficulty breathing, swelling of the face or throat). If these occur,
patients should be instructed to seek immediate emergency help [see CONTRAINDICATIONS
and WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop VIMOVO immediately if they
develop any type of rash and contact their health care provider as soon as
possible [see WARNINGS AND PRECAUTIONS].
Inform pregnant women to avoid use of VIMOVO and other
NSAIDs starting at 30 weeks gestation because of the risk of the premature
closure of the fetal ductus arteriosus [see WARNINGS AND PRECAUTIONS and
Use In Specific Populations].
Advise females of reproductive potential that NSAIDs,
including VIMOVO, may be associated with reversible infertility [see Use In Specific
To return to their healthcare provider if they have a
gastric symptoms while taking VIMOVO or after completing treatment [see WARNINGS
Acute Interstitial Nephritis
Advise patients to report to their health care provider
if they experience a decrease in the amount they urinate or have blood in their
urine [see WARNINGS AND PRECAUTIONS].
Clostridium Difficile-Associated Diarrhea
Advise patients to immediately report and seek care for
diarrhea that does not improve. This may be a sign of Clostridium difficile
associated diarrhea [see WARNINGS AND PRECAUTIONS].
Advise patients to report any sign or symptom of
osteoporosis (e.g., recent bone fracture, low bone density) to their health
care provider [see WARNINGS AND PRECAUTIONS].
Cutaneous And Systemic Lupus Erythematosus
Advise patients to immediately call their healthcare
provider any new or worsening of symptoms associated with cutaneous or systemic
lupus erythematosus [see WARNINGS AND PRECAUTIONS].
Cyanocobalamin (Vitamin B-12) Deficiency
Advise patients taking VIMOVO for long periods of time,
to report to their healthcare provider if they experience weakness, tiredness,
or light-headedness or rapid heartbeat and breathing or pale skin [see WARNINGS
Advise patients to immediately report and seek care for
any cardiovascular or neurological symptoms including palpitations, dizziness,
seizures, and tetany as these may be signs of hypomagnesemia [see WARNINGS
- Inform patients that the concomitant use of VIMOVO with
other NSAIDs or salicylates (e.g., diflunisal, salsalate) it is not recommended
due to the increased risk of gastrointestinal toxicity, and little or no
increase in efficacy [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Alert patients that NSAIDs may be present in the “over the counter” medications
for treatment of colds, fever or insomnia.
- Advise patients to report to their healthcare provider if
they start treatment with clopidogrel, St. John'sWort or rifampin; or, if they
take high-dose methotrexate [see WARNINGS AND PRECAUTIONS].
- Inform patients not to use low-dose aspirin concomitantly
with VIMOVO until they talk to their health care provider [see DRUG
- Inform patients that VIMOVO tablets should be swallowed
whole with liquid. Tablets should not be split, chewed, crushed or dissolved.
VIMOVO tablets should be taken at least 30 minutes before meals [see DOSAGE
- Patients should be instructed that if a dose is missed,
it should be taken as soon as possible. However, if the next scheduled dose is
due, the patient should not take the missed dose, and should be instructed to
take the next dose on time. Patients should be instructed not to take 2 doses
at one time to make up for a missed dose.
- Inform patients that antacids may be used while taking
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
A 2-year study was performed in rats to evaluate the
carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day
(0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1500
mg/day based on a body surface area comparison). The maximum dose used was 0.28
times the highest recommended human dose. No evidence of tumorigenicity was
The carcinogenic potential of esomeprazole was assessed
using omeprazole studies, of which esomeprazole is an enantiomer. In two
24-month oral carcinogenicity studies in rats, omeprazole at daily doses of
1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (about 0.41 to 34.2 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 3.36 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 mouse carcinogenicity study of
omeprazole did not show increased tumor occurrence, but the study was not
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.
Use In Specific Populations
Use of NSAIDs, including
VIMOVO, during the third trimester of pregnancy increases the risk of premature
closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIMOVO,
in pregnant women starting at 30 weeks of gestation (third trimester). There
are no adequate and well-controlled studies of VIMOVO in pregnant women.
VIMOVO contains naproxen and
esomeprazole magnesium. Esomeprazole is the S-isomer of omeprazole.
Data from observational studies
regarding potential embryofetal risks of NSAID use in women in the first or
second trimesters of pregnancy are inconclusive. In animal reproduction
studies, naproxen administered during organogenesis to rats and rabbits at
doses less than the maximum recommended human daily dose of 1500 mg/day showed
no evidence of harm to the fetus [see Data]. Based on animal data,
prostaglandins have been shown to have an important role in endometrial
vascular permeability, blastocyst implantation, and decidualization. In animal
studies, administration of prostaglandin synthesis inhibitors such as naproxen
resulted in increased pre-and post-implantation loss.
There are no human data for
esomeprazole. However, available epidemiologic data for omeprazole
(esomeprazole is the S-isomer of omeprazole) fail to demonstrate an increased
risk of major congenital malformations or other adverse pregnancy outcomes with
first trimester omeprazole use [see Data]. In animal studies with
administration of oral esomeprazole magnesium in rats 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 esomeprazole or 40 mg omeprazole. 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. 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.
Labor Or Delivery
There are no studies on the
effects of VIMOVO during labor or delivery. In animal studies, NSAIDs,
including naproxen, inhibit prostaglandin synthesis, cause delayed parturition,
and increase the incidence of stillbirth.
When used to delay preterm
labor, inhibitors of prostaglandin synthesis, including NSAIDs such naproxen,
may increase the risk of neonatal complications such as necrotizing
enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen
treatment given in late pregnancy to delay parturition has been associated with
persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin
E levels in preterm infants.
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.
retrospective cohort epidemiological study from the Swedish Medical Birth
Registry, covering approximately 99% of pregnancies, from 1995-99, 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 population.
retrospective cohort study covering all live births in Denmark from 1996 -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
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% 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.
There are no reproduction
studies in animals with VIMOVO, a combination of naproxen and esomeprazole.
Reproduction studies with
naproxen administered during the period of organogenesis have been performed in
rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500
mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26
times the maximum recommended human daily dose, based on body surface area
comparison), and mice at 170 mg/kg/day (0.56 times the maximum recommended
human daily dose based on body surface area comparison) with no evidence of
harm to the fetus due to the drug.
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 42 times an oral human dose of 40 mg esomeprazole or 40 mg
omeprazole on a body surface area basis) administered during organogenesis and
have revealed no evidence of harm to the fetus due to esomeprazole magnesium.
A pre-and postnatal
developmental toxicity study in rats with additional endpoints to evaluate bone
development were performed with esomeprazole magnesium at oral doses of 14 to
280 mg/kg/day (about 3.4 to 68 times a daily 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 a daily 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 the daily human dose of 40 mg on a body
surface area basis).
Effects on maternal bone were
observed in pregnant and lactating rats in the 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 basis).
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
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.
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
VIMOVO and any potential adverse effects on the breastfed infant from the drug
or from the underlying maternal condition.
Females And Males Of Reproductive
Based on the mechanism of
action, the use of prostaglandin-mediated NSAIDs, including VIMOVO, may delay
or prevent rupture of ovarian follicles that may lead to reversible infertility
in some women. Small studies in women treated with NSAIDs have also shown a
reversible delay in ovulation. Published animal studies have shown that
administration of prostaglandin synthesis inhibitors have the potential to
disrupt prostaglandin-mediated follicular rupture required for ovulation.
Consider withdrawal of NSAIDs, including VIMOVO, in women who have difficulties
conceiving or who are undergoing investigation of infertility.
The safety and effectiveness of
VIMOVO have been established in adolescent patients 12 years of age and older
weighing at least 38 kg for the symptomatic relief of JIA and to decrease the
risk of developing naproxen-associated gastric ulcers. Use of VIMOVO in this
age group is based on extrapolation of adequate and well-controlled studies in
adults and supported by a 6 month safety study including pharmacokinetic
assessment of naproxen and esomeprazole magnesium in 36 adolescent patients
with JIA. Based on the limited data, the plasma naproxen and plasma
esomeprazole concentrations were found to be within the range to that observed
to those found in healthy adults. The safety profile of VIMOVO in adolescent
patients with JIA was similar to adults with RA.
The safety and effectiveness of
VIMOVO in pediatric patients less than 12 years of age or less than 38 kg with
JIA 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
Elderly patients, compared to
younger patients, are at greater risk for NSAID-associated serious
cardiovascular, gastrointestinal, and/or renal adverse reactions. If the
anticipated benefit for the elderly patient outweighs these potential risks,
start dosing at the low end of the dosing range, and monitor patients for
adverse effects [see WARNINGS AND PRECAUTIONS].
Of the total number of patients
who received VIMOVO (n=1157) in clinical trials, 387 were ≥65 years of
age, of which 85 patients were 75 years and over. No meaningful differences in
efficacy or safety were observed between these subjects and younger subjects [see
Studies indicate that although
total plasma concentration of naproxen is unchanged, the unbound plasma
fraction of naproxen is increased in the elderly. Caution is advised when high
doses are required and some adjustment of dosage may be required in elderly
patients. As with other drugs used in the elderly, it is prudent to use the
lowest effective dose [see DOSAGE AND ADMINISTRATION and CLINICAL
Experience indicates that
geriatric patients may be particularly sensitive to certain adverse effects of
NSAIDs. Elderly or debilitated patients seem to tolerate peptic ulceration or
bleeding less well when these events do occur. Most spontaneous reports of
fatal GI events are in the geriatric population [see WARNINGS AND
Naproxen and its metabolites
are known to be substantially excreted by the kidney, and the risk of adverse
reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection, and it may be useful to monitor renal
function. Geriatric patients may be at a greater risk for the development of a
form of renal toxicity precipitated by reduced prostaglandin formation during
administration of NSAIDs [see WARNINGS AND PRECAUTIONS].
VIMOVO should be avoided in
patients with severe hepatic impairment because naproxen may increase the risk
of renal failure or bleeding and esomeprazole doses should not exceed 20 mg
daily in these patients [see DOSAGE AND ADMINISTRATION, WARNINGS
AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
including VIMOVO, are not recommended for use in patients with advanced renal
disease [see DOSAGE AND ADMINISTRATION, WARNINGS AND