Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Serotonin Syndrome
(Additions and/or revisions underlined)
Serotonin-norepinephrine reuptake
inhibitors (SNRIs) and selective-serotonin reuptake
inhibitors (SSRIs), including PRISTIQ, can precipitate serotonin
syndrome, a potentially life-threatening condition. The risk is increased with
concomitant use of other serotonergic drugs (including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan,
buspirone, amphetamines, and St. John’s Wort) and with drugs that impair
metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug
Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used
alone.
5.4 Increased Risk
of Bleeding
(Additions and/or revisions underlined)
Drugs that interfere with serotonin reuptake
inhibition, including PRISTIQ,
may increase the risk
of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs, warfarin, and other anticoagulants may add to this risk. Case reports
and epidemiological studies (case- control and cohort design) have demonstrated
an association between use of drugs that interfere with serotonin reuptake and
the occurrence of gastrointestinal bleeding. Based on data from the
published observational studies, exposure to SNRIs, particularly in the month
before delivery, has been associated with a less than 2-fold increase in the
risk of postpartum hemorrhage [see Use in Specific Populations (8.1)].
Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis,
hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Inform patients
about the increased risk of bleeding
associated with the concomitant use of
PRISTIQ and antiplatelet agents or anticoagulants. For patients taking
warfarin, carefully monitor coagulation indices when initiating, titrating, or
discontinuing PRISTIQ.
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
The following adverse
reaction has been identified during post-approval use of PRISTIQ. Because these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure:
Skin and subcutaneous tissue disorders – Stevens-Johnson syndrome
Gastrointestinal disorders – Pancreatitis acute
Cardiovascular system – Takotsubo cardiomyopathy
Respiratory, thoracic and mediastinal disorders - Anosmia,
hyposmia
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to antidepressants
during pregnancy. Healthcare providers are encouraged to register patients by
calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185.
Risk Summary
(Additions and/or revisions
underlined)
Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less
than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and
Precautions (5.4) and Clinical Considerations].
…
Maternal
Adverse Reactions
Exposure to PRISTIQ in
mid to late pregnancy may increase the risk for preeclampsia, and exposure to PRISTIQ in the month
before delivery may be associated with an increased risk of postpartum
hemorrhage [see Warnings and Precautions (5.4)]…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Suicidal Thoughts and
Behaviors
Advise patients and
caregivers to look for the emergence of suicidality, especially early during
treatment and when the dose is adjusted
up or down, and instruct
them to report such symptoms to the healthcare provider [see
Boxed Warning and Warnings and Precautions (5.1)].
Concomitant Medication
Advise patients taking
PRISTIQ not to use concomitantly other products containing desvenlafaxine or venlafaxine. Healthcare professionals should instruct
patients not to take
PRISTIQ with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping PRISTIQ before starting an
MAOI [see Contraindications (4)].
Serotonin Syndrome
(Additions and/or revisions
underlined)
Caution patients about
the risk of serotonin syndrome, particularly with the concomitant use of
PRISTIQ with other serotonergic agents (including triptans, tricyclic
antidepressants, opioids, lithium, amphetamines, tryptophan, buspirone, and St. John's Wort supplements) [see
Warnings and Precautions (5.2)].
MEDICATION GUIDE
(Extensive changes; please refer to label for complete
information)
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.1
Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients
5.2
Serotonin Syndrome
Serotonin-norepinephrine reuptake
inhibitors
(SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including
PRISTIQ, can precipitate serotonin syndrome, a potentially life-threatening
condition. The risk is increased with concomitant use of other serotonergic
drugs (including triptans, tricyclic antidepressants, fentanyl, lithium,
tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with
drugs that impair metabolism of serotonin, i.e., MAOIs Serotonin syndrome
can also occur when these drugs are used alone.
Serotonin syndrome signs and
symptoms may include mental status changes (e.g., agitation, hallucinations,
delirium, and coma) …
… The concomitant use of PRISTIQ with
MAOIs is contraindicated. In addition, do not initiate PRISTIQ in a
patient being treated with MAOIs such as linezolid or intravenous methylene
blue …
… Monitor all patients taking PRISTIQ
for the emergence of serotonin syndrome. Discontinue treatment with PRISTIQ and
any concomitant serotonergic agents immediately if the above symptoms occur,
and initiate supportive symptomatic treatment. If concomitant use of
PRISTIQ with other serotonergic drugs is clinically warranted, inform patients
of the increased risk for serotonin syndrome and monitor for symptoms.
5.4 Increased
Risk of Bleeding
Drugs that interfere with serotonin
reuptake inhibition,
including PRISTIQ, may increase the risk of bleeding events. Concomitant use of
aspirin … Inform patients about the risk of bleeding associated with the
concomitant use of PRISTIQ and antiplatelet agents or anticoagulants. For
patients taking warfarin, carefully monitor coagulation indices when
initiating, titrating, or discontinuing PRISTIQ.
5.5
Angle Closure Glaucoma
… in a patient with anatomically narrow
angles who does not have a patent iridectomy. Avoid use of antidepressants,
including PRISTIQ, in patients with untreated anatomically narrow angles.
5.7
Discontinuation Syndrome
Adverse reactions after discontinuation of
serotonergic antidepressants, particularly after abrupt discontinuation,
include: nausea, sweating, dysphoric mood, irritability, agitation,
dizziness, sensory disturbances (e.g., paresthesia, such as electric shock
sensations), tremor, anxiety, confusion, headache, lethargy, emotional
lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction
in dosage rather than abrupt cessation is recommended whenever possible.
6
Adverse Reactions
Additions
and/or reactions underlined:
7
Drug Interactions
Additions
and/or reactions underlined:
7.1
Drugs Having Clinically Important Interactions with PRISTIQ
Table
8: Clinically Important Drug Interactions with PRISTIQ
Newly
added table; please refer to label for complete information.
7.2
Drugs Having No Clinically Important Interactions with PRISTIQ
Based on pharmacokinetic studies,
no dosage adjustment is required for drugs that are mainly
metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized
by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when
administered concomitantly with PRISTIQ.
8
Use in Specific Populations
8.1 Pregnancy
PLLR
conversion; additions and/or revisions underlined:
Pregnancy Exposure Registry
There is a pregnancy exposure
registry that monitors pregnancy outcomes in women exposed to antidepressants
during pregnancy. Healthcare providers are encouraged to register patients by
calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185.
Risk summary
There are no published studies on
PRISTIQ in pregnant women; however published epidemiologic studies of
pregnant women exposed to venlafaxine, the parent compound, have not reported a
clear association with adverse developmental outcomes. There are risks
associated with untreated depression in pregnancy and with exposure to SNRIs
and SSRIs, including PRISTIQ, during pregnancy.
In reproductive developmental studies in
rats and rabbits treated with desvenlafaxine succinate, there was no evidence
of teratogenicity at a plasma exposure (AUC) that is up to 19-times
(rats) and 0.5-times (rabbits) the exposure at an adult human dose of
100 mg per day. However, fetotoxicity and pup deaths were observed in rats
at 4.5-times the AUC exposure observed with an adult human dose of 100 mg
per day.
The estimated 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
2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated
maternal and/or embryo/fetal risk
A prospective longitudinal study of 201
women …
Maternal
adverse reactions
Exposure to SNRIs in mid to late pregnancy
may increase the risk for preeclampsia, and exposure to SNRIs near delivery may
increase the risk for postpartum hemorrhage.
Fetal/Neonatal
adverse reactions
Exposure to SNRIs or SSRIs in late
pregnancy may lead to an increased risk for neonatal complications requiring
prolonged hospitalization, respiratory support, and tube feeding. Monitor
neonates who were exposed to PRISTIQ in the third trimester of pregnancy for
drug discontinuation syndrome.
Human
Data
Published epidemiological studies of
pregnant women exposed to the parent compound venlafaxine have not reported a
clear association with major birth defects or miscarriage. Methodological
limitations of these observational studies include possible exposure and
outcome misclassification, lack of adequate controls, adjustment for
confounders, and confirmatory studies; therefore, these studies cannot
establish or exclude any drug-associated risk during pregnancy.
Retrospective cohort studies based on
claims data have shown an association between venlafaxine use and preeclampsia,
compared to depressed women who did not take an antidepressant during
pregnancy. One study that assessed venlafaxine exposure in the second trimester
or first half of the third trimester and preeclampsia showed an increased risk
compared to unexposed depressed women (adjusted (adj) RR 1.57, 95% CI
1.29-1.91). Preeclampsia was observed at venlafaxine doses equal to or greater
than 75 mg/day and a duration of treatment greater than 30 days. Another study
that assessed venlafaxine exposure in gestational weeks 10-20 and preeclampsia
showed an increased risk at doses equal to or greater than 150 mg/day.
Available data are limited by possible outcome misclassification and possible
confounding due to depression severity and other confounders.
Retrospective cohort studies based on
claims data have suggested an association between venlafaxine use near the time
of delivery or through delivery and postpartum hemorrhage. One study showed an
increased risk for postpartum hemorrhage when venlafaxine exposure occurred
through delivery, compared to unexposed depressed women (adj RR 2.24 (95% CI
1.69-2.97). There was no increased risk in women who were exposed to
venlafaxine earlier in pregnancy. Limitations of this study include possible
confounding due to depression severity and other confounders. Another study
showed an increased risk for postpartum hemorrhage when SNRI exposure occurred
for at least 15 days in in the last month of pregnancy or through delivery,
compared to unexposed women (adj RR 1.64-1.76). The results of this study may
be confounded by the effects of depression.
Neonates exposed to SNRIs or SSRIs, late
in the third trimester …
Animal
Data
… These doses were associated with a
plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC
exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal
ossification was delayed in rats in association with maternal toxicity at the
highest dose, with an AUC exposure at the no-effect dose that is
4.5-times the AUC exposure at an adult human dose of 100 mg per day.
… The cause of these deaths is not known. The
AUC exposure at the no-effect dose for rat pup mortality was 4.5-times
the AUC exposure at an adult human dose of 100 mg per day. Post-weaning
growth and reproductive performance of the progeny were not affected by
maternal treatment with desvenlafaxine succinate at exposures 19 times the
AUC exposure at an adult human dose of 100 mg per day.
8.2 Lactation
PLLR
conversion; additions and/or revisions underlined:
Available limited data from published
literature show low levels of desvenlafaxine in human milk, and have not
shown adverse reactions in breastfed infants. There are no data on the
effects of desvenlafaxine on milk production.
The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for
PRISTIQ and any potential adverse effects on the breastfed child from PRISTIQ or
from the underlying maternal condition.
Data
A lactation study was conducted in 10
breastfeeding women (at a mean of 4.3 months post- partum) who were being
treated with a 50-150 mg daily dose of desvenlafaxine for postpartum
depression. Sampling was performed at steady state (up to 8 samples) over a 24
hour dosing period, and included foremilk and hindmilk. The mean relative
infant dose was calculated to be 6.8% (range of 5.5-8.1%). No adverse reactions
were seen in the infants.
8.4 Pediatric Use
Additions
and/or revisions underlined:
The safety and effectiveness of PRISTIQ
have not been established in pediatric patients for the treatment of MDD.
Efficacy was not demonstrated in two
adequate and well controlled, 8-week, randomized, double-blind, placebo-controlled,
parallel group studies conducted in 587 patients (7 to 17 years of age) for the
treatment of MDD.
Antidepressants, such as PRISTIQ, increase
the risk of suicidal thoughts and behaviors in pediatric patients.
PRISTIQ was associated with a decrease in
body weight in placebo-controlled trials in pediatric patients with MDD. The
incidence of weight loss (greater than or equal to 3.5% of baseline weight) was
22%, 14%, and 7% for patients treated with low dose PRISTIQ, high dose PRISTIQ,
and placebo, respectively.
The risks associated with longer term
PRISTIQ use were assessed in 6-month, open-label extension studies in pediatric
patients (7 to 17 years of age) with MDD. Pediatric patients (7 to 17 years of
age) had mean changes in weight that approximated expected changes, based on
data from age- and sex-matched peers.
In clinical trials, when compared to adult
patients receiving the same dose of PRISTIQ, exposure to desvenlafaxine was
similar in adolescent patients 12 to 17 years of age, and was about 30% higher
in pediatric patients 7 to 11 years of age.
Juvenile
Animal Studies
In a juvenile animal study, male and
female rats were treated with desvenlafaxine (75, 225 and 675 mg/kg/day)
starting on postnatal day (PND) 22 through 112. Behavioral deficits (longer
time immobile in a motor activity test, longer time swimming in a straight
channel test, and lack of habituation in an acoustic startle test) were
observed in males and females but were reversed after a recovery period. A No
Adverse Effect Level (NOAEL) was not identified for these deficits. The Low
Adverse Effect Level (LOAEL) was 75 mg/kg/day which was associated with plasma
exposure (AUC) twice the levels measured with a pediatric dose of 100 mg/day.
In a second juvenile animal study, male
and female rats were administered desvenlafaxine (75, 225 or 675 mg/kg/day) for
8-9 weeks starting on PND 22 and were mated with naïve counterparts. Delays in
sexual maturation and decreased fertility, number of implantation sites and
total live embryos were observed in treated females at all doses. The LOAEL for
these findings is 75 mg/kg/day which was associated with an AUC twice the
levels measured with a pediatric dose of 100 mg/day. These findings were
reversed at the end of a 4-week recovery period. The relevance of these
findings to humans is not known.
8.6 Renal Impairment
Additions
and/or revisions underlined:
Adjust the maximum
recommended
dosage in patients with moderate or severe renal impairment
(CLcr 15 to 50 mL/min, C-G), or
end-stage renal disease (CLcr less
than 15 mL/min,
C-G).
8.7 Hepatic Impairment
Additions
and/or revisions underlined:
Adjust the maximum recommended dosage
in patients with moderate to severe hepatic
impairment (Child-Pugh score 7 to 15).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
This
has been revised; please refer to label for complete information.
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Advise the patient to read the FDA-approved
patient labeling (Medication Guide).
Suicidal
Thoughts and Behaviors
Advise patients and caregivers to look for
the emergence of suicidality, especially early during treatment and when the
dose is adjusted up or down, and instruct them to report such symptoms to
the healthcare provider.
Increased
Risk of Bleeding
Inform patients about the concomitant use
of PRISTIQ with NSAIDs, aspirin, other antiplatelet drugs, warfarin, or other
coagulants because the combined use of has been associated with an increased
risk of bleeding. Advise patients to inform their health care providers if they
are taking or planning to take any prescription or over-the-counter medications
that increase the risk of bleeding.
Discontinuation
Advise patients not to abruptly stop
taking PRISTIQ without talking first with their healthcare professional.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Serotonin Syndrome
(additions
underlined)
The development of a potentially life-threatening serotonin syndrome has
been reported with SNRIs and SSRIs, including PRISTIQ, alone but particularly with
concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.
John's Wort), and with drugs that impair metabolism of serotonin (in particular,
MAOIs, both those intended to treat psychiatric disorders and also others, such
as linezolid and intravenous methylene blue).
…
If concomitant use of PRISTIQ with other serotonergic drugs, including triptans,
tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines,
tryptophan, and St. John's Wort is clinically warranted, patients should be made
aware of a potential increased risk for serotonin syndrome, particularly during
treatment initiation and dose increases.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(addition
underlined)
Serotonin Syndrome
Caution patients about the risk
of serotonin syndrome, particularly with the concomitant use of PRISTIQ with other
serotonergic agents (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, amphetamines, tryptophan, buspirone, and St. John's
Wort supplements).
MEDICATION GUIDE
Serotonin syndrome
(addition
underlined)
Rare, but potentially life-threatening
conditions called serotonin syndrome can happen when medicines such as PRISTIQ
are taken with certain other medicines. Serotonin syndrome can cause serious
changes in how your brain, muscles, heart and blood vessels, and digestive
system work. Especially tell your healthcare provider if you take the following:
- amphetamine
- medicines to treat migraine headaches known
as triptans
- medicines used to treat mood, anxiety, psychotic, or thought disorders,
including tricyclics, lithium, selective serotonin reuptake inhibitors (SSRIs),
serotonin norepinephrine reuptake inhibitors (SNRIs), or other dopamine antagonists,
such as metoclopramide
- silbutramine
- Tramadol
- St. John’s Wort
- MAOIs (including linezolid, an antibiotic
and intravenous methylene blue
- tryptophan supplements
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