Included as part of the "PRECAUTIONS" Section
Suicidal Thoughts And Behaviors
BRISDELLE is not approved for any psychiatric condition.
Antidepressants, including those that contain an SSRI, increase the risk of suicidal thinking and behavior
(suicidality) in pediatric and young adult patients when used to treat major depressive disorder (MDD)
and other psychiatric disorders. There is limited information regarding suicidality in women who use
BRISDELLE for treatment of VMS. The BRISDELLE trials excluded women with a presence or
history of previous psychiatric disorders.
Consider discontinuing BRISDELLE in patients with worsening depression or those who experience
emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
All patients being treated with BRISDELLE should be observed closely for clinical worsening,
suicidality, and unusual changes in behavior, especially during the initial few months of treatment.
Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, and mania have been reported in patients being treated with
antidepressants for MDD as well as for other psychiatric and nonpsychiatric indications. Although a
causal link between the emergence of such symptoms and either the worsening of depression and/or the
emergence of suicidal impulses has not been established, there is concern that such symptoms may
represent precursors to emerging suicidality.
Families and caregivers of patients being treated with BRISDELLE should be alerted about the
need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
and the other symptoms described above, as well as the emergence of suicidality, and to report
such symptoms immediately to healthcare providers.
The development of a potentially life-threatening serotonin syndrome has been reported with SSRIs,
including paroxetine, alone but particularly with concomitant use of 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 depression and others such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,
diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Monitor patients for the emergence of serotonin syndrome.
The concomitant use of BRISDELLE with MAOIs is contraindicated. Do not start BRISDELLE in a
patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports
with methylene blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of
methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There
may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or
intravenous methylene blue in a patient taking BRISDELLE. BRISDELLE should be discontinued before
initiating treatment with the MAOI [see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION] .
If concomitant use of BRISDELLE with other serotonergic drugs (e.g., triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) is
clinically warranted, consider the increased risk of serotonin syndrome and carefully observe the
patient, particularly during treatment initiation [see CONTRAINDICATIONS, DRUG INTERACTIONS].
Discontinue BRISDELLE and any concomitant serotonergic agents immediately if the above
events occur and initiate supportive symptomatic treatment.
Potential Impact On Tamoxifen Efficacy
It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect
on the efficacy of tamoxifen. Some studies have shown that the efficacy of tamoxifen, as measured by
the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a
result of paroxetine’s irreversible inhibition of CYP2D6 [see DRUG INTERACTIONS] . However, other
studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of
breast cancer, weigh the likely benefit of BRISDELLE for treating VMS vs. the risk of possible
decreased tamoxifen effectiveness, and consider avoiding the concomitant use of BRISDELLE for
SSRIs, including BRISDELLE, may increase the risk of bleeding events. Concomitant use of aspirin,
nonsteroidal anti-inflammatory drugs (NSAIDs), 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. Bleeding events related to SSRIs have ranged from ecchymosis, hematoma,
epistaxis, and petechiae to life-threatening hemorrhages. Caution patients about the risk of bleeding
associated with the concomitant use of BRISDELLE and NSAIDs, aspirin, or other drugs that affect
coagulation [see DRUG INTERACTIONS] .
The pupillary dilation that occurs following use of many antidepressants and BRISDELLE may trigger
an angle closure attack in a patient with anatomically narrow angles who does not have a patent
Hyponatremia may occur as a result of treatment with SSRIs, including BRISDELLE. Elderly patients
may be at greater risk. In many cases, the hyponatremia appears to be the result of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110
mmol/L have been reported in patients using SSRIs. Also, patients taking diuretics or who are volumedepleted
can be at greater risk. Consider discontinuation of BRISDELLE in patients with symptomatic
hyponatremia and institute appropriate medical intervention.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment,
confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with
more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest,
Epidemiological studies on bone fracture risk following exposure to SSRIs have reported an
association between SSRI treatment and fractures. It is unknown to what extent fracture risk is directly
attributable to SSRI treatment. If a BRISDELLE-treated patient presents with unexplained bone pain,
point tenderness, swelling, or bruising, consider the possibility of a fragility fracture.
Screening Patients For Bipolar Disorder And Monitoring For Mania/Hypomania
BRISDELLE is only indicated for the treatment of moderate to severe VMS and is not approved for use
in treating either depression or bipolar depression. However, prior to initiating treatment with
BRISDELLE, all patients should be adequately screened to determine if they are at risk for bipolar
disorder; such screening should include a detailed psychiatric history, including a family history of
suicide, bipolar disorder, and depression. It is generally believed (though not established in controlled
trials) that use of an antidepressant alone may increase the likelihood of precipitation of a mixed/manic
episode in patients at risk for bipolar disorder.
In premarketing testing of paroxetine, seizures occurred in 0.1% of paroxetine-treated patients. Use
BRISDELLE cautiously in patients with a history of seizures or with conditions that potentially lower
the seizure threshold. Evaluate and consider discontinuing use in any patient who develops seizures.
The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is
characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or
stand still usually associated with subjective distress. This is most likely to occur within the first few
weeks of treatment. Discontinue treatment with BRISDELLLE if akathisia occurs.
Potential For Cognitive And Motor Impairment
BRISDELLE has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned
about operating hazardous machinery, including motor vehicles, until they are reasonably certain that the
drug treatment does not affect them adversely.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
Instruct patients to read the Medication Guide before starting therapy with BRISDELLE and to reread it
each time the prescription is renewed.
- Advise patients, their families, and their caregivers to look for the emergence of suicidality,
especially early during treatment [see BOX WARNING and WARNINGS AND PRECAUTIONS].
- Instruct patients not to take BRISDELLE with an MAOI or within 14 days of stopping an MAOI and
allow 14 days after stopping BRISDELLE before starting an MAOI [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS] .
- Advise patients not to take BRISDELLE with thioridazine or pimozide [see CONTRAINDICATIONS] .
- Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of
BRISDELLE with triptans, tricyclic antidepressants, linezolid, tramadol, amphetamines, St. John’s
Wort, lithium, tryptophan supplements, other serotonergic agents, or antipsychotic drugs [see
WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS] .
- Caution patients that efficacy of tamoxifen may be reduced when administered concomitantly and
counsel them about the likely benefit of paroxetine for treating VMS vs. the risk of possible
decreased tamoxifen effectiveness [see WARNINGS AND PRECAUTIONS] .
- Caution patients about the concomitant use of BRISDELLE and NSAIDs, aspirin, warfarin, and other
anticoagulants because combined use of drugs that interfere with serotonin reuptake has been
associated with an increased risk of bleeding [see WARNINGS AND PRECAUTIONS].
- Advise patients that taking BRISDELLE can cause mild pupillary dilation, which in susceptible
individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost
always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated
definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
Patients may wish to be examined to determine whether they are susceptible to angle closure, and
have a prophylactic procedure (e.g., iridectomy), if they are susceptible [See WARNINGS AND PRECAUTIONS].
- Caution patients about the risk of hyponatremia, particularly elderly patients and those who are taking
diuretics or are volume-depleted [see WARNINGS AND PRECAUTIONS].
- Inform patients that there is the possibility for an increased risk of fracture [see WARNINGS AND PRECAUTIONS] .
- Advise patients, their families, and their caregivers to observe for signs of activation of
mania/hypomania [see WARNINGS AND PRECAUTIONS] .
- Advise patients to notify their physician if they become pregnant during therapy [see
CONTRAINDICATIONS and Use In Specific Populations] .Caution patients about operating
hazardous machinery, including motor vehicles, until they are reasonably certain that paroxetine
therapy does not affect their ability to engage in such activities [see WARNINGS AND PRECAUTIONS] .
- Advise patients to inform their healthcare provider if they are taking, or plan to take, any
prescription or over-the-counter drugs, including herbal supplements, because there is a potential
for interaction with paroxetine [see DRUG INTERACTIONS] .
- Advise patients that paroxetine, the active ingredient in BRISDELLE, is also the active ingredient in
certain other drugs and these medications should not be taken concomitantly [see INDICATIONS AND USAGE and DRUG INTERACTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25
mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). The doses used in these carcinogenicity studies
were approximately 16 (mouse) and 26 (rat) times the MHRD for VMS. There was a significantly
greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and
4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
trend across groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not
affected. Although there was a dose-related increase in the number of tumors in mice, there was no
drug-related increase in the number of mice with tumors. The relevance of these findings to humans is
Paroxetine produced no genotoxic effect in a battery of 5 in vitro and 2 in vivo assays that included the
following: bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis
assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human
lymphocytes and in a dominant lethal test in rats.
Impairment Of Fertility
A reduced pregnancy rate was found in reproduction studies in rats at a paroxetine dose of 15
mg/kg/day, which is 19 times the MRHD for VMS on an mg/m2 basis. Irreversible lesions occurred in
the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions
consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the
seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (65 times and 32 times
the MHRD for VMS on an mg/m2 basis, respectively).
Use In Specific Populations
Pregnancy Category X
BRISDELLE is contraindicated in pregnant women because menopausal VMS does not occur during
pregnancy and paroxetine can cause fetal harm. Epidemiological studies have shown that infants
exposed to paroxetine in the first trimester of pregnancy may have an increased risk of cardiovascular
malformations. Cardiac malformations are a common congenital abnormality. These data would suggest
that the risk of a cardiac abnormality following paroxetine exposure in the first trimester may increase
the risk from 1% to 2%. Exposure to SSRIs in late pregnancy may lead to an increased risk for neonatal
complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or
persistent pulmonary hypertension of the newborn (PPHN). No teratogenicity was seen in reproductive
development studies conducted in rats and rabbits. However, an increase in rat pup deaths was seen
during the first 4 days of lactation when dosing occurred during the last trimester of gestation and
continued throughout lactation, at a dose approximately equal to the maximum recommended human dose
(MRHD) for VMS (7.5 mg) on an mg/m basis. If this drug is used during pregnancy, or if the patient
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a
First-Trimester Pregnancy Exposure
- Epidemiologic studies which include data from the Swedish National Registry, a retrospective
cohort study using United Healthcare data and a meta-analysis of studies (1992-2008) have shown a
less than 2-fold increased risk of cardiac malformations, primarily ventricular septal and atrial septal
defects, with first-trimester paroxetine exposure. Two case-control studies using separate
databases with > 9000 birth defect cases and > 4000 controls showed 7 and 6 paroxetine-exposed
infants respectively, with right ventricular outflow tract obstructions, a 2- to 3-fold increased risk.
An increase in overall congenital malformations with first-trimester paroxetine use was not
observed in all studies.
Third-Trimester Pregnancy Exposure
- Neonates exposed to SSRIs late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise
immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis,
apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia,
hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are
consistent with either a direct toxic effect of SSRIs or, possibly, a drug discontinuation syndrome. It
should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see
WARNINGS AND PRECAUTIONS] .
- Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary
hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1000 live births in the general
population and is associated with substantial neonatal morbidity and mortality. In a retrospective
case-control study of 377 women whose infants were born with PPHN and 836 women whose
infants were born healthy, the risk for developing PPHN was approximately 6-fold higher for
infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been
exposed to antidepressants during pregnancy. There is currently no corroborative evidence
regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that
has investigated the potential risk. The study did not include enough cases with exposure to
individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits
administered during organogenesis. These doses are approximately 65 (rat) and 16 (rabbit) times the
maximum recommended human dose (MRHD) for VMS on an mg/m2 basis. There were no teratogenic
effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when
dosing occurred during the last trimester of gestation and continued throughout lactation. This effect
occurred at a dose of 1 mg/kg/day or approximately equal to the MRHD for VMS on an mg/m2 basis.
The no-effect dose for rat pup mortality was not determined. The cause of these deaths is unknown.
Paroxetine is excreted in human milk. Because of the potential for serious adverse reactions in nursing
infants from BRISDELLE, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established; BRISDELLE is not indicated in
the pediatric population.
Clinical studies of BRISDELLE did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Elderly patients may have elevated
paroxetine plasma concentrations compared to younger patients. However, no BRISDELLE dose
adjustment is considered necessary in elderly patients [see CLINICAL PHARMACOLOGY] .
SSRIs have been associated with cases of clinically significant hyponatremia in elderly patients, who
may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS] .
No BRISDELLE dose adjustment is considered necessary in patients with renal impairment [see CLINICAL PHARMACOLOGY] .
No BRISDELLE dose adjustment is considered necessary in patients with liver impairment [see CLINICAL PHARMACOLOGY] .