(Additions and/or
revisions underlined)
…
Serious
Skin Reactions, Including DRESS
Advise
patients to stop VOLTAREN immediately if they develop any type of rash or
fever and 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
VOLTAREN, 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 VOLTAREN and other NSAIDs, starting at 30 weeks
gestation because of the risk of the premature closure of the fetal ductus
arteriosus. If treatment with VOLTAREN 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).
…
(Additions and/or
revisions underlined)
…
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 5700 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 VOLTAREN. 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 VOLTAREN and evaluate the patient immediately.
Fetal
Toxicity
Premature
Closure of Fetal Ductus Arteriosus
Avoid
use of NSAIDs, including VOLTAREN, in pregnant women at about 30-weeks’
gestation and later. NSAIDs, including VOLTAREN, increase the risk of premature
closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal
Renal Impairment
Use
of NSAIDs, including VOLTAREN, 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 VOLTAREN use to the lowest effective dose and shortest duration possible.
Consider ultrasound monitoring of amniotic fluid if VOLTAREN treatment extends
beyond 48 hours. Discontinue VOLTAREN if oligohydramnios occurs and follow up
according to clinical practice (see PRECAUTIONS; Pregnancy).
…
(Additions and/or
revisions underlined)
Risk Summary
Use of NSAIDs, including VOLTAREN, 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 VOLTAREN use between about
20 and 30 weeks of gestation, and avoid VOLTAREN 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 VOLTAREN, 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
VOLTAREN in pregnant women.
Data from observational studies regarding potential embryo-fetal
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 VOLTAREN, 200
mg/day, 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 post-implantation 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 VOLTAREN, 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 VOLTAREN treatment extends beyond 48 hours, consider monitoring
with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue
VOLTAREN 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 post-marketing 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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