Approved Drug Label (PDF)
5
Warnings and Precautions
5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
(Newly added
subsection)
Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS) has been reported in patients taking NSAIDs such as NALFON.
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 NALFON
and evaluate the patient immediately.
5.11 Fetal Toxicity
(Subsection title revised; Additions and/or revisions underlined)
Premature
Closure of Fetal Ductus Arteriosus
Avoid
use of NSAIDs, including NALFON, in pregnant women at about 30 weeks
gestation and later. NSAIDs, including NALFON, increase the risk of
premature closure of the fetal ductus arteriosus at approximately this
gestational age.
Oligohydramnios/Neonatal
Renal Impairment
Use
of NSAIDs, including NALFON, 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 NALFON use to the lowest effective dose and shortest duration possible.
Consider ultrasound monitoring of amniotic fluid if NALFON treatment extends
beyond 48 hours.
Discontinue
NALFON if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or
revisions underlined)
Risk Summary
Use of NSAIDs, including NALFON, 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 NALFON use between about 20
and 30 weeks of gestation, and avoid NALFON use at about 30 weeks of gestation
and later in pregnancy (see Clinical
Considerations, Data)
Premature Closure of Fetal Ductus Arteriosus
Use of NSAIDs,
including NALFON, 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.
Data from
observational studies regarding other potential embryofetal risks of
NSAID use in women in the first or second trimesters of pregnancy are
inconclusive. In animal reproduction studies, embryo-fetal lethality and skeletal
abnormalities were noted in offspring of pregnant rabbits following oral administration
of fenoprofen during organogenesis at 0.6 times the maximum human daily dose of
3200 mg/day. However, there were no major malformations noted following oral
administration of fenoprofen calcium to pregnant rats and rabbits during organogenesis
at exposures up to 0.3 and 0.6 times the maximum human daily dose of 3200 mg/day.
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 fenoprofen, 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 NALFON, can cause
premature closure of the fetal ductus arteriosus (see Data).
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 NALFON treatment extends beyond 48 hours, consider
monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs,
discontinue NALFON and follow up according to clinical practice (see Data).
Labor or Delivery
There are no studies on the effects of NALFON during
labor or delivery. In animal studies, NSAIDS, including fenoprofen, inhibit
prostaglandin synthesis, cause delayed parturition, and increase the incidence
of stillbirth.
Data
Human Data
There are no adequate and well-controlled studies of
NALFON 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.
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.
…
8.2 Lactation
(Additions and/or
revisions underlined)
Risk
Summary
In
a published study, after a dose of 600 mg every 6 hours for 4 days in
postpartum mothers, breastmilk NALFON levels were reportedly 1.6% of those in
maternal plasma. Because there is little published experience with
fenoprofen during breastfeeding, other agents may be preferred, especially
while nursing a newborn or preterm infant. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for NALFON and any potential adverse effects on the breastfed infant from
the fenoprofen or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
Before
taking NSAIDS, tell your healthcare provider about all of your medical
conditions, including if you:
have
liver or kidney problems
have
high blood pressure
have
asthma
are
pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of
pregnancy or later may harm your unborn baby. If you need to take NSAIDs for
more than 2 days when you are between 20 and 30 weeks of pregnancy, your
healthcare provider may need to monitor the amount of fluid in your womb around
your baby. You should not take NSAIDs
after about 30 weeks of pregnancy.
- are
breastfeeding or plan to breast feed.
…
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
Advise
the patient to read the FDA-approved patient labeling (Medication Guide) that
accompanies each prescription dispensed. Inform patients, families, or their
caregivers of the following information before initiating therapy with NALFON
and periodically during the course of ongoing therapy.
Cardiovascular
Thrombotic Events
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 and Precautions (5.1)].
Gastrointestinal
Bleeding, 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 and Precautions (5.2)].
Hepatotoxicity
Inform
patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness,
and “flu-like” symptoms). If these occur, instruct patients to stop NALFON and
seek immediate medical therapy [see
Warnings and Precautions (5.3)].
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
healthcare provider if such symptoms occur [see
Warnings and Precautions (5.5)].
Anaphylactic
Reactions
Inform
patients of the signs of an anaphylactic reaction (e.g., difficulty breathing,
swelling of the face or throat). Instruct patients to seek immediate emergency
help if these occur [see
Contraindications (4) and Warnings and Precautions (5.7)].
Serious
Skin Reactions, including DRESS
Advise
patients to stop taking NALFON immediately if they develop any type of
rash or fever and to contact their healthcare provider as soon as
possible [see Warnings and Precautions (5.9),
(5.10)].
Female
Fertility
Advise
females of reproductive potential who desire pregnancy that NSAIDs, including
NALFON, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]
Fetal
Toxicity
Inform
pregnant women to avoid use of NALFON and other NSAIDs starting at 30 weeks
gestation because of the risk of the premature closing of the fetal ductus
arteriosus. If treatment with NALFON 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 and Precautions (5.11) and Use in Specific Populations (8.1)].
Avoid
Concomitant Use of NSAIDs
Inform
patients that the concomitant use of NALFON with other NSAIDs or salicylates
(e.g., diflunisal, salsalate) is not recommended due to the increased risk of
gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug
Interactions (7)]. Alert patients that NSAIDs may be present in “over the
counter” medications for treatment of colds, fever, or insomnia.
Use
of NSAIDS and Low-Dose Aspirin
Inform
patients not to use low-dose aspirin concomitantly with NALFON until they talk
to their healthcare provider [see Drug
Interactions (7)].
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