(Additions and/or
revisions underlined)
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Serious
Skin Reactions, Including DRESS
Advise
patients to stop CATAFLAM immediately if they develop any type of rash or
fever and to contact their healthcare provider as soon as possible
(see WARNINGS; Serious Skin Reactions).
Female
Fertility
Advise
females of reproductive potential who desire pregnancy that NSAIDs, including CATAFLAM,
may be associated with a reversible delay in ovulation (see PRECAUTIONS;
Carcinogenesis, Mutagenesis, Impairment of Fertility).
Fetal
Toxicity
Inform
pregnant women to avoid use of CATAFLAM and other NSAIDs, starting at 30 weeks
gestation because of the risk of the premature closure of the fetal ductus
arteriosus. If treatment with CATAFLAM is needed for a pregnant woman
between about 20 to 30 weeks gestation, advise her that she may need to be
monitored for oligohydramnios, if treatment continues for longer than 48 hours
(see WARNINGS; Fetal Toxicity, PRECAUTIONS, Pregnancy).
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(Additions and/or
revisions underlined)
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Hepatotoxicity
In clinical trials of diclofenac-containing
products, meaningful elevations (i.e., more than 3 times the upper limit
of normal [ULN]) of aspartate aminotransferase (AST) (also known as SGOT)
were observed in about 2% of approximately 5,700 patients at some time during
diclofenac treatment (alanine aminotransferase [ALT] was not measured in
all studies).
…
Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS) has been reported in patients taking NSAIDs, such as CATAFLAM.
Some of these events have been fatal or life-threatening. DRESS typically,
although not exclusively, presents with fever, rash, lymphadenopathy, and/or
facial swelling. Other clinical manifestations may include hepatitis, nephritis,
hematological abnormalities, myocarditis, or myositis.
Sometimes symptoms of DRESS may resemble an acute
viral infection. Eosinophilia is often present. Because this disorder is
variable in its presentation, other organ systems not noted here may be
involved. It is important to note that early manifestations of
hypersensitivity, such as fever or lymphadenopathy, may be present even though
rash is not evident. If such signs or symptoms are present, discontinue
CATAFLAM and evaluate the patient immediately.
Fetal
Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including CATAFLAM, in pregnant
women at about 30 weeks’ gestation and later. NSAIDs, including
CATAFLAM, increase the risk of premature closure of the fetal ductus arteriosus
at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including CATAFLAM, at about 20 weeks
gestation or later in pregnancy may cause fetal renal dysfunction leading to
oligohydramnios and, in some cases, neonatal renal impairment. These adverse
outcomes are seen, on average, after days to weeks of treatment, although
oligohydramnios has been infrequently reported as soon as 48 hours after NSAID
initiation. Oligohydramnios is often, but not always, reversible with treatment
discontinuation. Complications of prolonged oligohydramnios may, for example,
include limb contractures and delayed lung maturation. In some postmarketing
cases of impaired neonatal renal function, invasive procedures, such as
exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20
weeks and 30 weeks gestation, limit CATAFLAM use to the lowest effective dose
and shortest duration possible. Consider ultrasound monitoring of amniotic
fluid if CATAFLAM treatment extends beyond 48 hours. Discontinue CATAFLAM if
oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
…
(Additions and/or
revisions underlined)
Risk
Summary
Use
of NSAIDs, including CATAFLAM can cause premature closure of the fetal
ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and,
in some cases, neonatal renal impairment. Because of these risks, limit dose
and duration of CATAFLAM use between about 20 and 30 weeks of gestation, and
avoid CATAFLAM use at about 30 weeks of gestation and later in pregnancy (see
WARNINGS; Fetal Toxicity).
Premature Closure
of Fetal Ductus Arteriosus
Use of NSAIDs, including CATAFLAM, at about 30 weeks
gestation or later in pregnancy increases the risk of premature closure
of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs at about 20 weeks gestation or later
in pregnancy has been associated with cases of fetal renal dysfunction leading
to oligohydramnios, and in some cases, neonatal renal impairment.
There are no adequate and well-controlled studies of
CATAFLAM in pregnant women.
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, no evidence of
teratogenicity was observed in mice, rats, or rabbits given diclofenac during
the period of organogenesis at doses up to approximately 0.5, 0.5, and 1 times,
respectively, the maximum recommended human dose (MRHD) of CATAFLAM, despite
the presence of maternal and fetal toxicity at these doses (see Data).
Based on published 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 diclofenac,
resulted in increased pre- and postimplantation loss. Prostaglandins
also have been shown to have an important role in fetal kidney development. In
published animal studies, prostaglandin synthesis inhibitors have been reported
to impair kidney development when administered at clinically relevant doses.
The estimated background risk of major birth defects
and miscarriage for the indicated population(s) is 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.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Premature Closure of Fetal Ductus Arteriosus:
Avoid use of NSAIDs in women at about 30 weeks
gestation and later in pregnancy, because NSAIDs, including CATAFLAM, can cause
premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal
Toxicity).
Oligohydramnios/Neonatal Renal Impairment:
If an NSAID is necessary at about 20 weeks gestation
or later in pregnancy, limit the use to the lowest effective dose and shortest
duration possible. If CATAFLAM treatment extends beyond 48 hours, consider
monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs,
discontinue CATAFLAM and follow up according to clinical practice (see
WARNINGS; Fetal Toxicity).
Data
Human Data
Premature Closure of Fetal Ductus Arteriosus:
Published literature reports that the use of NSAIDs
at about 30 weeks of gestation and later in pregnancy may cause premature
closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment:
Published studies and postmarketing reports describe
maternal NSAID use at about 20 weeks gestation or later in pregnancy associated
with fetal renal dysfunction leading to oligohydramnios, and in some cases,
neonatal renal impairment. These adverse outcomes are seen, on average, after
days to weeks of treatment, although oligohydramnios has been infrequently
reported as soon as 48 hours after NSAID initiation. In many cases, but not
all, the decrease in amniotic fluid was transient and reversible with cessation
of the drug. There have been a limited number of case reports of maternal NSAID
use and neonatal renal dysfunction without oligohydramnios, some of which were
irreversible. Some cases of neonatal renal dysfunction required treatment with
invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing
studies and reports include lack of a control group; limited information
regarding dose, duration, and timing of drug exposure; and concomitant use of
other medications. These limitations preclude establishing a reliable estimate of
the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because
the published safety data on neonatal outcomes involved mostly preterm infants,
the generalizability of certain reported risks to the full-term infant exposed
to NSAIDs through maternal use is uncertain.
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