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Prevacid NapraPAC Warnings, Precautions, Pregnancy, Nursing, Abuse - Naproxen and Lansoprazole
Prevacid NapraPAC Warnings, Precautions, Pregnancy, Nursing, Abuse - Naproxen and Lansoprazole
WARNINGS
NAPROSYN
Risk of GI Ulceration, Bleeding and Perforation With
NSAID Therapy
Serious gastrointestinal toxicity such as bleeding, ulceration
and perforation can occur at any time, with or without warning symptoms,
in patients treated chronically with NSAID therapy. Although minor upper
gastrointestinal problems, such as dyspepsia, are common, usually developing
early in therapy, physicians should remain alert for ulceration and bleeding
in patients treated chronically with NSAIDs even in the absence of previous
GI tract symptoms. In patients observed in clinical trials of several
months to 2 years’ duration, symptomatic upper GI ulcers, gross bleeding
or perforation appear to occur in approximately 1% of patients treated
for 3 to 6 months and in about 2% to 4% of patients treated for 1 year.
Physicians should inform patients about the signs and/or
symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date with naproxen have not identified any
subset of patients not at risk of developing peptic ulceration and bleeding.
Except for a prior history of serious GI events and other risk factors
known to be associated with peptic ulcer disease, such as alcoholism,
smoking, etc., no risk factors (e.g., age, sex) have been associated with
increased risk. Elderly or debilitated patients seem to tolerate ulceration
or bleeding less well than other individuals and most spontaneous reports
of fatal GI events are in this population. Studies to date are inconclusive
concerning the relative risk of various NSAIDs in causing such reactions.
High doses of any NSAID probably carry a greater risk of these reactions,
although controlled clinical trials showing this do not exist in most
cases. In considering the use of relatively large doses (within the recommended
dosage range), sufficient benefit should be anticipated to offset the
potential increased risk of GI toxicity.
Physicians should consider alternative treatment to NSAIDs
in patients who have experienced a serious gastrointestinal toxicity associated
with NSAID use. For patients who require the use of an NSAID, coadministration
of PREVACID 15 mg Delayed-Release Capsules with NSAIDs has been proven
effective to reduce the risk of gastric ulcers associated with NSAID use
in patients with a previous history of documented gastric ulcers. (See
CLINICAL STUDIES, PREVACID® NapraPACTM (375
or 500), Risk Reduction of NSAID-Associated Gastric Ulcer.)
PRECAUTIONS
General
NAPROSYN
NAPROXEN-CONTAINING PRODUCTS SUCH AS NAPROSYN®
(NAPROXEN) TABLETS, EC-NAPROSYN® (NAPROXEN) DELAYED-RELEASE
TABLETS, ANAPROX®/ANAPROX DS® (NAPROXEN
SODIUM) TABLETS, NAPROSYN® (NAPROXEN) SUSPENSION, ALEVE®
(NAPROXEN SODIUM), AND OTHER NAPROXEN PRODUCTS INCLUDING PREVACID®
NapraPACTM(375 or 500), SHOULD NOT BE USED CONCOMITANTLY SINCE
THEY ALL CIRCULATE IN THE PLASMA AS THE NAPROXEN ANION.
NAPROSYN cannot be expected to substitute for corticosteroids
or to treat corticosteroid insufficiency. If the steroid dose is reduced
or eliminated during therapy, the steroid dosage should be reduced slowly
and the patient should be observed closely for any evidence of adverse
effects, including adrenal insufficiency and exacerbation of symptoms
of arthritis.
Patients with initial hemoglobin values of 10 grams or
less who are to receive long-term therapy should have hemoglobin values
determined periodically.
The antipyretic and anti-inflammatory activities of the
drug may reduce fever and inflammation, thus diminishing their utility
as diagnostic signs in detecting complications of presumed noninfectious,
noninflammatory painful conditions.
Because of adverse eye findings in animal studies with
drugs of this class, it is recommended that ophthalmic studies be carried
out if any change or disturbance in vision occurs.
PREVACID
Symptomatic response to therapy with lansoprazole does
not preclude the presence of gastric malignancy.
Information for patients
Each convenience package of PREVACID®
NapraPACTM (375 or 500) contains sufficient product for seven
days of treatment. Each daily dose consists of one PREVACID 15 mg capsule
and two NAPROSYN tablets, either 375 mg or 500 mg. Take the PREVACID capsule
and one NAPROSYN tablet in the morning before eating with a glass of water.
Take the second NAPROSYN tablet in the evening with a glass of water.
NAPROSYN, like other drugs of this class, is not free
of side effects. The side effects of this formulation can cause discomfort
and, rarely, there are more serious side effects, such as gastrointestinal
bleeding, which may result in hospitalization and even fatal outcomes.
PREVACID when taken with naproxen has been shown to reduce the risk of
NSAID-associated gastric ulcers in patients with a history of ulcer.
NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often
essential agents in the management of arthritis and have a major role
in the treatment of pain. Naproxen as NAPROSYN is indicated for the treatment
of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
Physicians may wish to discuss with their patients the
potential risks (see WARNINGS,
PRECAUTIONS and
ADVERSE REACTIONS)
and likely benefits of naproxen treatment, particularly when it is used
for less serious conditions where treatment without NSAIDs may represent
an acceptable alternative to both the patient and physician.
Caution should be exercised by patients whose activities
require alertness if they experience drowsiness, dizziness, vertigo or
depression during therapy with naproxen.
Renal Effects
NAPROSYN
As with other nonsteroidal anti-inflammatory drugs, long-term
administration of naproxen to animals has resulted in renal papillary
necrosis and other abnormal renal pathology. In humans, there have been
reports of acute interstitial nephritis, hematuria, proteinuria and occasionally
nephrotic syndrome associated with naproxen-containing products and other
NSAIDs since they have been marketed.
A second form of renal toxicity has been seen in patients
taking naproxen as well as other nonsteroidal anti-inflammatory drugs.
In patients with prerenal conditions leading to a reduction in renal blood
flow or blood volume, where the renal prostaglandins have a supportive
role in the maintenance of renal perfusion, administration of a nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin
formation and precipitate overt renal decompensation. Patients at greatest
risk of this reaction are those with impaired renal function, heart failure,
liver dysfunction, those taking diuretics and the elderly. Discontinuation
of nonsteroidal antiinflammatory therapy is typically followed by recovery
to the pretreatment state.
Naproxen and its metabolites are eliminated primarily
by the kidneys; therefore, the drug should be used with caution in patients
with significantly impaired renal function, and the monitoring of serum
creatinine and/or creatinine clearance is advised in these patients. Caution
should be used if the drug is given to patients with creatinine clearance
of less than 20 mL/minute because accumulation of naproxen metabolites
has been seen in such patients.
Chronic alcoholic liver disease and probably other diseases
with decreased or abnormal plasma proteins (albumin) reduce the total
plasma concentration of naproxen, but the plasma concentration of unbound
naproxen is increased. Caution is advised when high doses are required
and some adjustment of dosage may be required in these patients. It is
prudent to use the lowest effective dose.
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.
Hepatic Function
NAPROSYN
As with other nonsteroidal anti-inflammatory drugs, borderline
elevations of one or more liver tests may occur in up to 15% of patients.
These abnormalities may progress, may remain essentially unchanged, or
may be transient with continued therapy. The SGPT (ALT) test is probably
the most sensitive indicator of liver dysfunction. Meaningful (3 times
the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in
controlled clinical trials in less than 1% of patients. A patient with
symptoms and/or signs suggesting liver dysfunction or in whom an abnormal
liver test has occurred, should be evaluated for evidence of the development
of more severe hepatic reaction while on therapy with naproxen. Severe
hepatic reactions, including jaundice and cases of fatal hepatitis, have
been reported with naproxen as with other nonsteroidal anti-inflammatory
drugs. Although such reactions are rare, if abnormal liver tests persist
or worsen, if clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (eg, eosinophilia, rash,
etc.), naproxen should be discontinued.
Fluid Retention and Edema
NAPROSYN
Peripheral edema has been observed in some patients receiving
naproxen.
Laboratory Tests
NAPROSYN
Because serious GI tract ulceration and bleeding can
occur without warning symptoms, physicians should follow patients chronically
treated with naproxen for signs and symptoms of ulceration and bleeding
and should inform them of the importance of this follow-up and what they
should do if certain signs and symptoms do appear (see WARNINGS,
NAPROSYN Risk of GI Ulcerations, Bleeding and Perforation With NSAID Therapy).
Carcinogenesis, Mutagenesis, Impairment of Fertility
NAPROSYN
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
(50, 100, and 150 mg/m2). The maximum dose used was 0.28 times
the systemic exposure to humans at the recommended dose. No evidence of
tumorigenicity was found.
PREVACID
In two 24-month carcinogenicity studies, Sprague-Dawley
rats were treated orally with doses of 5 to 150 mg/kg/day, about 1 to
40 times the exposure on a body surface (mg/m2) basis, of a
50-kg person of average height (1.46 m2 body surface area)
given the recommended human dose of 30 mg/day (22.2 mg/m2).
Lansoprazole produced dose-related gastric enterochromaffin-like (ECL)
cell hyperplasia and ECL cell carcinoids in both male and female rats.
It also increased the incidence of intestinal metaplasia of the gastric
epithelium in both sexes. In male rats, lansoprazole produced a dose-related
increase of testicular interstitial cell adenomas. The incidence of these
adenomas in rats receiving doses of 15 to 150 mg/kg/day (4 to 40 times
the recommended human dose based on body surface area) exceeded the low
background incidence (range = 1.4 to 10%) for this strain of rat. Testicular
interstitial cell adenoma also occurred in 1 of 30 rats treated with 50
mg/kg/day (13 times the recommended human dose based on body surface area)
in a 1-year toxicity study.
In a 24-month carcinogenicity study, CD-1 mice were treated
orally with doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended
human dose based on body surface area. Lansoprazole produced a dose-related
increased incidence of gastric ECL cell hyperplasia. It also produced
an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma).
The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40
to 80 times the recommended human dose based on body surface area) and
female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended
human dose based on body surface area) exceeded the ranges of background
incidences in historical controls for this strain of mice. Lansoprazole
treatment produced adenoma of rete testis in male mice receiving 75 to
600 mg/kg/day (10 to 80 times the recommended human dose based on body
surface area).
Lansoprazole was not genotoxic in the Ames test, the
ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the
in vivo mouse micronucleus test or the rat bone marrow cell chromosomal
aberration test. It was positive in in vitro human lymphocyte chromosomal
aberration assays.
Lansoprazole at oral doses up to 150 mg/kg/day (40 times
the recommended human dose based on body surface area) was found to have
no effect on fertility and reproductive performance of male and female
rats.
Pregnancy: Teratogenic Effects
Pregnancy Category B
PREVACID® NapraPACTM (375 or
500)
There are no adequate and well-controlled studies in
pregnant women. Because animal reproduction studies are not always predictive
of human response, PREVACID® NapraPACTM (375
or 500) should not be used during pregnancy unless clearly needed.
NAPROSYN
Reproduction studies have been performed in rats at 20
mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure),
rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human
systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day,
0.28 times the human systemic exposure) with no evidence of impaired fertility
or harm to the fetus due to the drug. There are no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, naproxen should not be used during
pregnancy unless clearly needed. PREVACID
Teratology studies have been performed in pregnant rats
at oral doses up to 150 mg/kg/day (40 times the recommended human dose
based on body surface area) and pregnant rabbits at oral doses up to 30
mg/kg/day (16 times the recommended human dose based on body surface area)
and have revealed no evidence of impaired fertility or harm to the fetus
due to lansoprazole.
Nonteratogenic Effects
NAPROSYN
There is some evidence to suggest that when inhibitors
of prostaglandin synthesis are used to delay preterm labor there is an
increased 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. Because of the known effect of drugs of this
class on the human fetal cardiovascular system (closure of ductus arteriosus),
use during third trimester should be avoided.
Nursing Mothers
PREVACID® NapraPACTM (375 or
500)
No studies were conducted in this population with PREVACID®
NapraPACTM, however, because of the possible adverse effects
of prostaglandin-inhibiting drugs on neonates, use of PREVACID®
NapraPACTM (375 or 500) in nursing mothers should be avoided.
NAPROSYN
The naproxen anion has been found in the milk of lactating
women at a concentration of approximately 1% of that found in plasma.
Because of the possible adverse effects of prostaglandin-inhibiting drugs
on neonates, use in nursing mothers should be avoided.
PREVACID
Lansoprazole or its metabolites are excreted in the milk
of rats. It is not known whether lansoprazole is excreted in human milk.
Because many drugs are excreted in human milk, because of the potential
for serious adverse reactions in nursing infants from lansoprazole, and
because of the potential for tumorigenicity shown for lansoprazole in
rat carcinogenicity studies, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.
Pediatric Use
PREVACID® NapraPACTM (375 or
500)
The safety and effectiveness of PREVACID®
NapraPACTM (375 or 500) in pediatric patients have not been
established.
Geriatric Use
NAPROSYN
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.
PREVACID
The incidence rates of adverse events and laboratory
test abnormalities are also similar to those seen in younger patients.
For elderly patients, dosage and administration of lansoprazole need not
be altered.
Use in Women
PREVACID
Over 4,000 women were treated with lansoprazole. Ulcer
healing rates in females were similar to those in males. The incidence
rates of adverse events were also similar to those seen in males.
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