Approved Drug Label (PDF)
5
Warnings and Precautions
PRECAUTIONS
Newly added information:
Pregnancy: Advise pregnant
females that use of TRANXENE
late in pregnancy can result
in sedation (respiratory depression, lethargy,
hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors,
inconsolable crying, and feeding difficulties) in newborns (see Warnings, Neonatal Sedation and
Withdrawal Syndrome and Precautions, Pregnancy). Instruct patients to
inform their healthcare provider if they are pregnant.
Advise patients that there is a pregnancy exposure registry that monitors pregnancy
outcomes in women exposed to TRANXENE during pregnancy (see Precautions,
Pregnancy).
Nursing: Advise patients that breastfeeding is not recommended during treatment with TRANXENE (see Precautions, Nursing
Mothers).
. . .
Pregnancy:
Pregnancy Exposure Registry
There is a pregnancy exposure
registry that monitors
pregnancy outcomes in women exposed to psychiatric medications,
including TRANXENE, during pregnancy. Healthcare providers are encouraged to
register patients calling the National Pregnancy Registry for Psychiatric
Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.
Risk Summary
Neonates born to mothers using benzodiazepines late
in pregnancy have been reported to experience
symptoms of sedation
and/or neonatal withdrawal (see WARNINGS:
Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations). Available data from
published observational studies
of pregnant women
exposed to benzodiazepines do not report a clear association with
benzodiazepines and major birth defects (see
Data).
The background risk of major birth defects
and miscarriage for the indicated
population 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
Benzodiazepines cross the placenta and may produce
respiratory depression, hypotonia, and sedation in neonates. Monitor neonates
exposed to TRANXENE during pregnancy or labor for signs of sedation,
respiratory depression, hypotonia, and feeding problems. Monitor neonates
exposed to TRANXENE during pregnancy for signs of withdrawal. Manage these
neonates accordingly (see WARNINGS:
Neonatal Sedation and Withdrawal Syndrome).
Data
Human Data
Published data from observational studies
on the use of benzodiazepines during pregnancy do not report a clear association with
benzodiazepines and major birth defects. Although early studies reported an
increased risk of congenital malformations with diazepam and chlordiazepoxide,
there was no consistent pattern noted. In addition, the majority of more recent
case-control and cohort studies of benzodiazepine use during pregnancy, which
were adjusted for confounding exposures to alcohol, tobacco and other
medications, have not confirmed these findings.
Animal Data
In animal reproduction studies, oral administration of clorazepate to pregnant rats and rabbits at doses up to 150 and 15 mg/kg, respectively, did
not cause fetal toxicities or malformation. However, the sedative effects of
high dose clorazepate interfered with the maternal care of the offspring.
Nursing Mothers:
Risk Summary
Clorazepate and its active metabolite, nordiazepam,
are present in breast milk. There are reports
of sedation, poor feeding and poor weight
gain in infants exposed to benzodiazepines
through breast milk. The effects of clorazepate on milk production are unknown. Because of the potential for
serious adverse reactions, including sedation and withdrawal symptoms in
infants, advise patients that breastfeeding is not recommended during treatment
with TRANXENE.
WARNINGS
Newly added information:
Neonatal Sedation
and Withdrawal Syndrome: Use of TRANXENE
late in pregnancy can result in sedation (respiratory depression, lethargy,
hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors,
inconsolable crying, and feeding difficulties) in the neonate (see
PRECAUTIONS: Pregnancy). Monitor neonates exposed to TRANXENE during pregnancy or labor for signs of sedation and
monitor neonates exposed to TRANXENE during pregnancy for signs of withdrawal;
manage these neonates accordingly.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
Additions and revisions underlined:
Taking TRANXENE
late in pregnancy may cause your baby to have symptoms of sedation
(breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness,
irritability, restlessness, shaking, excessive crying, feeding problems).
Tell your healthcare provider right away if you become pregnant or think you are pregnant during
treatment with TRANXENE.
There is a pregnancy registry for women who take TRANXENE during pregnancy. The purpose of the registry is to collect
information about the health of you and your baby.
If you become pregnant during treatment with TRANXENE, talk to your healthcare provider about registering
with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1- 866-961-2388- or visiting https://womensmentalhealth.org/pregnancyregistry/.
. . .
TRANXENE passes into breast milk.
Talk to your healthcare provider about the best way to feed your baby if you take TRANXENE.
Breastfeeding is not recommended during treatment with TRANXENE.
Approved Drug Label (PDF)
Boxed Warning
(Additions and/or revisions underlined)
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE,
MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL
REACTIONS
• Concomitant use of benzodiazepines and opioids may result
in profound
sedation, respiratory depression, coma, and death. Reserve
concomitant
prescribing of these drugs in patients for whom alternative
treatment
options are inadequate. Limit dosages and durations to the
minimum
required. Follow patients for signs and symptoms of
respiratory
depression and sedation (See WARNINGS and PRECAUTIONS).
• The use of benzodiazepines, including TRANXENE, exposes
users to risks of
abuse, misuse, and addiction, which can lead to overdose
or death. Abuse and
misuse of benzodiazepines commonly involve concomitant use
of other
medications, alcohol, and/or illicit substances, which is
associated with an
increased frequency of serious adverse outcomes. Before
prescribing
TRANXENE and throughout out treatment, assess each
patient’s risk for
abuse, misuse, and addiction (See WARNINGS).
• The continued use of benzodiazepines, including
TRANXENE, may lead to
clinically significant physical dependence. The risks of
dependence and
withdrawal increase with longer treatment duration and
higher daily dose.
Abrupt discontinuation or rapid dosage reduction of
TRANXENE after
continued use may precipitate acute withdrawal reactions,
which can be life threatening.
To reduce the risk of withdrawal reactions, use a gradual
taper to
discontinue TRANXENE or reduce the dosage (See DOSAGE AND
ADMINISTRATION and WARNINGS).
5
Warnings and Precautions
Warnings
(Newly
added information)
Abuse, Misuse, and
Addiction: The use of benzodiazepines, including TRANXENE,
exposes users to the risks
of abuse, misuse,
and addiction, which can
lead to overdose or death.
Abuse and misuse of benzodiazepines
often (but not always) involve the use of doses greater than the maximum
recommended dosage and commonly involve
concomitant use of other medications, alcohol, and/or illicit substances,
which is associated with an increased frequency
of serious adverse outcomes, including
respiratory depression, overdose, or death (see DRUG ABUSE
AND DEPENDENCE: Abuse).
Before prescribing TRANXENE and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using
a standardized screening tool). Use of TRANXENE, particularly in patients
at elevated risk, necessitates counseling about the risks
and proper use of
TRANXENE along with monitoring for signs and symptoms of abuse, misuse, and addiction.
Prescribe the lowest effective dosage; avoid or minimize concomitant
use of CNS depressants and
other substances associated with abuse,
misuse, and addiction (e.g., opioid
analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer
them for) early treatment,
as appropriate.
Dependence and Withdrawal Reactions: To reduce
the risk of withdrawal reactions,
use a gradual taper to discontinue
TRANXENE or reduce the dosage (a patient-specific plan
should be used to taper
the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation
of Dosage
Reduction of TRANXENE).
Patients
at an increased risk of withdrawal
adverse reactions after benzodiazepine discontinuation
or rapid dosage reduction include
those who take higher dosages,
and those who have had longer durations of use.
Acute Withdrawal Reactions
The continued use of benzodiazepines, including TRANXENE,
may lead to clinically significant physical dependence.
Abrupt discontinuation or rapid dosage reduction of TRANXENE after continued use, or
administration of flumazenil (a
benzodiazepine antagonist)
may precipitate acute withdrawal
reactions, which can be life-threatening (e.g.,
seizures) (see DRUG ABUSE
AND DEPENDENCE: Dependence).
Protracted Withdrawal
Syndrome
In some cases, benzodiazepine
users have developed a protracted
withdrawal syndrome with withdrawal symptoms lasting weeks to more
than 12 months (see DRUG ABUSE AND
DEPENDENCE).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Information for Patients
Advise the patient to read the
FDA-approved patient labeling
(Medication Guide).
Risks from Concomitant Use with Opioids
Advise both patients and caregivers about
the risks of potentially fatal respiratory depression and sedation
when TRANXENE is used with
opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not
to drive or operate heavy machinery
until the effects of concomitant use with
the opioid have been determined (see WARNINGS, Risks from Concomitant
Use with Opioids and PRECAUTIONS, Drug
Interactions).
Abuse, Misuse, and
Addiction: Inform patients
that the use of
TRANXENE, even at recommended dosages, exposes users
to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially
when used in combination with other
medications (e.g., opioid analgesics),
alcohol, and/or illicit substances. Inform patients about
the signs and symptoms
of benzodiazepine abuse, misuse,
and addiction; to seek medical
help if they develop these signs and/or symptoms; and
on the proper disposal of unused drug (see WARNINGS
and DRUG ABUSE AND DEPENDENCE).
Withdrawal Reactions: Inform patients that the
continued use of TRANXENE may lead to clinically
significant physical dependence
and that abrupt discontinuation or rapid dosage reduction
of TRANXENE may precipitate acute withdrawal reactions, which can be life- threatening. Inform patients that
in some cases, patients taking benzodiazepines
have developed a protracted withdrawal syndrome with withdrawal
symptoms lasting weeks to more
than 12 months. Instruct patients
that discontinuation or
dosage reduction of TRANXENE
may require a slow taper (see WARNINGS
and DRUG ABUSE AND DEPENDENCE).
Medication Guide
(Extensive
changes; please refer to label)
Approved Drug Label (PDF)
Boxed Warning
(new
section added)
WARNING: RISKS FROM CONCOMITANT USE
WITH OPIOIDS
Concomitant
use of benzodiazepines and opioids may result in profound sedation, respiratory
depression, coma, and death.
• Reserve concomitant
prescribing of these drugs for use in patients for whom alternative treatment
options are inadequate.
• Limit dosages and
durations to the minimum required.
• Follow patients for signs
and symptoms of respiratory depression and sedation.
5
Warnings and Precautions
WARNINGS
(additions
underlined)
Risks from Concomitant Use with
Opioids: Concomitant use of benzodiazepines, including
TRANXENE, and opioids may result in profound sedation, respiratory depression,
coma, and death. Because of these risks, reserve concomitant prescribing of
these drugs for use in patients for whom alternative treatment options are
inadequate.
Observational
studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of drug-related mortality compared to use of
opioids alone. If a decision is made to prescribe TRANXENE concomitantly with
opioids, prescribe the lowest effective dosages and minimum durations of
concomitant use, and follow patients closely for signs and symptoms of respiratory
depression and sedation. In patients already
receiving
an opioid analgesic, prescribe a lower initial dose of TRANXENE than indicated
in the absence of an opioid and titrate based on clinical response. If an
opioid is initiated in a patient already taking TRANXENE, prescribe a lower
initial dose of the opioid and titrate based upon clinical response.
Advise
both patients and caregivers about the risks of respiratory depression and
sedation when TRANXENE is used with opioids. Advise patients not to drive or
operate heavy machinery until the effects of concomitant use with the opioid
have been determined
Table 1: Risk by indication for
antiepileptic drugs in the pooled analysis
(table
revised; please refer to label)
7
Drug Interactions
(additions
underlined)
The
concomitant use of benzodiazepines and opioids increases the risk of
respiratory depression because of actions at different receptor sites in the
CNS that control respiration. Benzodiazepines interact at GABAA sites and
opioids interact primarily at mu receptors. When benzodiazepines and opioids
are combined, the potential for benzodiazepines to significantly worsen
opioid-related respiratory depression exists. Limit dosage and duration of
concomitant use of benzodiazepines and opioids, and monitor patients closely
for respiratory depression and sedation.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions
underlined)
•TRANXENE
is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines,
alcohol, or other central nervous system depressants (including street drugs)
can cause severe drowsiness, breathing problems (respiratory depression), coma
and death.
What is TRANXENE?
It is not
known if TRANXENE is safe and effective in children less than 9 years
of age.
Before you take TRANXENE, tell your
healthcare provider about all your medical conditions including, if you:
·
have liver or kidney problems
·
have or have had depression, mood problems, or
suicidal thoughts or behavior
·
have a history of abnormal thinking and behavior
(psychotic reactions)
Tell your healthcare provider about
all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
Taking
TRANXENE with certain other medicines can cause side effects or affect how well
TRANXENE or the other medicines work. Do not start or stop other
medicines without talking to your healthcare provider.
How should I take TRANXENE?
•Take
TRANXENE exactly as your healthcare provider tells you to take it.
Your healthcare provider will tell you how much TRANXENE to take and when to
take it.
•Your
healthcare provider may change your dose if needed. Do not change your
dose of TRANXENE
without
talking to your healthcare provider.
•Do not
stop taking TRANXENE without first talking to your healthcare provider.
Stopping TRANXENE
suddenly
can cause serious problems.
•If you
take too much TRANXENE, call your healthcare provider or go to the nearest
hospital emergency room right away.
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