Approved Drug Label (PDF)
5
Warnings and Precautions
5.16 Increased Risk of Bleeding
Additions
and/or revisions underlined:
…
Based
on data from the published observational studies, exposure to SSRIs,
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
reactions related to SNRIs and SSRIs use have ranged from ecchymoses,
hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients
should be cautioned about the increased risk of bleeding associated with
the concomitant use of SYMBYAX and NSAIDs,
aspirin, or other drugs that affect coagulation [see Drug Interactions (7.4)].
5.6 Serotonin Syndrome
Additions and/or revisions underlined:
Selective serotonin reuptake inhibitors (SSRIs),
including SYMBYAX, 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 (4.1), Drug Interactions (7.1)]. Serotonin
syndrome can also occur when these drugs are used alone.
…
The
concomitant use of SYMBYAX with MAOIs is contraindicated. In addition, do
not initiate SYMBYAX in a patient being treated with MAOIs such as
linezolid or intravenous methylene blue. No reports involved the administration
of methylene blue by other routes (such as oral tablets or local tissue
injection). If it is necessary to initiate treatment with an MAOI such as
linezolid or intravenous methylene blue in a patient taking SYMBYAX,
discontinue SYMBYAX before initiating treatment with the MAOI [see Contraindications (4.1) and Drug
Interations (7.1)].
Monitor
all
patients taking SYMBYAX for the emergence of serotonin syndrome. Discontinue
treatment
with
SYMBYAX and any concomitant serotonergic agents immediately if the above
symptoms occur, and initiate supportive symptomatic treatment. If concomitant
use of SYMBYAX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for
serotonin syndrome and monitor for symptoms.
6
Adverse Reactions
Additions and/or
revisions underlined:
…
…
6.2 Postmarketing
Experience
Additions
and/or revisions underlined:
…
Fluoxetine: anosmia,
aplastic anemia, cholestatic jaundice, drug reaction with eosinophilia and
systemic symptoms (DRESS), eosinophilic pneumonia3, erythema multiforme,
violent behavior3, atrial fibrillation3, cataract, cerebrovascular accident 3,
epidermal necrolysis, erythema nodosum, heart arrest3, hepatic
failure/necrosis, hypoglycemia, hyposmia, kidney failure, memory impairment,
optic neuritis, pulmonary hypertension, Stevens-Johnson syndrome.
Olanzapine: diabetic coma,
jaundice, random triglyceride levels of greater than or equal to1000 mg/dL,
restless legs syndrome, stuttering4, salivary hypersecretion, allergic
reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria),
diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or
vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
…
7
Drug Interactions
7.3 Other Serotonergic Drugs
Additions
and/or revisions underlined:
The
concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans,
tricyclic antidepressants, opioids, lithium, buspirone, amphetamines,
tryptophan,
and St. John's Wort) with SYMBYAX increases the risk of serotonin
syndrome. Monitor patients for signs and symptoms of serotonin syndrome,
particularly during treatment initiation and dosage increases. If serotonin
syndrome occurs, consider discontinuation of SYMBYAX and/or concomitant serotonergic drugs [see
Warnings and Precautions (5.6)].
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
…
Risk Summary
Based on data from published observational studies,
exposure to SSRIs, 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
(5.16) and Clinical Considerations].
…
Maternal Adverse Reactions
Use of SYMBYAX in the month before delivery may be
associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.16)].
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Serotonin
Syndrome
Patients
should be cautioned about the risk of serotonin syndrome with the concomitant
use of SYMBYAX and other serotonergic agents including triptans, tricyclic
antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines,
and St. John’s Wort [see
Contraindications (4.1) and Warnings and Precautions (5.6), and Drug
Interactions (7.3)]. Patients should be advised of the signs and symptoms
associated with serotonin syndrome that may include mental status changes
(e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, dizziness, diaphoresis, flushing,
hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea). Patients
should be cautioned to seek medical care immediately if they experience these
symptoms.
…
Increased
Risk of
Bleeding
Patients
should be cautioned about the concomitant use of SYMBYAX and NSAIDs, aspirin,
warfarin, or other drugs that affect coagulation since the combined use of
psychotropic drugs that interfere with serotonin reuptake and these agents have
been associated with an increased risk of bleeding [see Warnings and Precautions (5.16)]. Patients should be advised
to call their doctor if they experience any increased or unusual bruising or
bleeding while taking SYMBYAX.
…
MEDICATION GUIDE
Additions and/or revisions underlined:
…
Before
starting SYMBYAX, tell your doctor about
all the medicines that you take, including
…
Tramadol,
fentanyl, meperidine, methadone, or other opioids
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.26 Sexual Dysfunction
(Newly added subsection)
![]()
Use of SSRIs, including fluoxetine a
component of SYMBYAX, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male
patients, SYMBYAX use may result in ejaculatory delay or failure, decreased
libido, and erectile dysfunction. In female patients, SYMBYAX use may result in
decreased libido and delayed or absent orgasm.
It
is important for prescribers to inquire about sexual function prior to
initiation of SYMBYAX and to inquire specifically about changes in sexual
function during treatment, because sexual function may not be spontaneously
reported. When evaluating changes in sexual function, obtaining a detailed
history (including timing of symptom onset) is important because sexual
symptoms may have other causes, including the underlying psychiatric disorder.
Discuss potential management strategies to
support patients in making informed decisions about treatment.
5.5 Metabolic Changes
(Additions and/or
revisions underlined)
…
Table
11: Weight Gain with SYMBYAX Use in a Single Relapse Prevention Study in Adults
…
6
Adverse Reactions
(Addition of the
following to the bulleted line listing)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
Sexual problems
(dysfunction): Taking selective serotonin reuptake (SSRIs), including
fluoxetine, a component of SYMBYAX, may cause sexual problems.
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
…
Sexual
Dysfunction
Advise
patients that use of SYMBYAX may cause symptoms of sexual dysfunction in both
male and female patients. Inform patients that they should discuss any changes
in sexual function and potential management strategies with their healthcare
provider [see Warnings and Precautions
(5.26)].
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
…
Other
Adverse Reactions Observed with Olanzapine or Fluoxetine Monotherapy
The
following adverse reactions were not observed in SYMBYAX-treated patients
during premarketing clinical studies but have been reported with olanzapine or
fluoxetine monotherapy: Bruxism, dysuria, esophageal ulcer,
gynecological bleeding, headache, hypotension, neutropenia, sudden unexpected
death3 and sweating.
…
6.2 Postmarketing Experience
(Additions and/or
revisions underlined)
The
following adverse reactions have been identified during post-approval use of
SYMBYAX, Fluoxetine, or Olanzapine monotherapy. Because these reactions
are reported voluntarily from a population of uncertain size, it is difficult
to reliably estimate their frequency or evaluate a causal relationship to drug
exposure.
Adverse
reactions reported since market introduction that were temporally (but not
necessarily causally) related to SYMBYAX, fluoxetine, or olanzapine
therapy include the following:
SYMBYAX: rhabdomyolysis
and venous thromboembolic events (including pulmonary embolism and deep venous
thrombosis)
Fluoxetine:
aplastic anemia, cholestatic jaundice, eosinophilic pneumonia3, erythema
multiforme, violent behavior3, atrial fibrillation3, cataract, cerebrovascular
accident 3, epidermal necrolysis, erythema nodosum, heart arrest3, hepatic
failure/necrosis, hypoglycemia, kidney failure, memory impairment, optic
neuritis, pulmonary hypertension, Stevens- Johnson syndrome.
Olanzapine:
diabetic coma, jaundice, random triglyceride levels of greater than or equal to
1000 mg/dL, restless legs syndrome, stuttering4, salivary hypersecretion,
allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or
urticaria), diabetic ketoacidosis, discontinuation reaction (diaphoresis,
nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS).
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion,
please refer to label for complete information)
8.2 Lactation
(PLLR conversion)
Risk Summary
Data
from published literature report the presence of olanzapine, fluoxetine, and
norfluoxetine in human milk (see Data). There
are reports of excess sedation, irritability, poor feeding and extrapyramidal
symptoms (tremors and abnormal muscle movements) in infants exposed to
olanzapine through breast milk and reports of agitation, irritability, poor
feeding and poor weight gain in infants exposed to fluoxetine through breast
milk (see Clinical Considerations). There
is no information on the effects of olanzapine or fluoxetine and their
metabolites on milk production.
The
developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for SYMBYAX and any potential adverse effects
on the breastfed child from SYMBYAX or the underlying maternal condition.
Clinical
Considerations
Infants
exposed to SYMBYAX should be monitored for agitation, irritability, poor
feeding, poor weight gain, excess sedation, and extrapyramidal symptoms
(tremors and abnormal muscle movements).
Data
A
study of nineteen nursing mothers on fluoxetine with daily doses of 10-60 mg
showed that fluoxetine was detectable in 30
8.3 Females and
Males of Reproductive Potential
(PLLR conversion)
Infertility
Females
Based
on the pharmacologic action of olanzapine (dopamine D2 receptor blockade),
treatment with SYMBYAX may result in an increase in serum prolactin levels, which
may lead to a reversible reduction in fertility in females of reproductive
potential [see Warnings and Precautions
(5.22)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions
underlined)
…
SYMBYAX
may not be right for you. Before starting SYMBYAX, tell your doctor about all
your medical conditions, including if you have or had any of the following:
…
are
pregnant or plan to become pregnant. It is not known if SYMBYAX will harm your
unborn baby. Talk to your healthcare provider about the benefits and risks
of treating depression during pregnancy.
If you become pregnant while taking SYMBYAX, talk to
your healthcare provider about registering with the National Pregnancy Registry
for Psychiatric Medications at 1-866-961- 2388 or visit https://womensmentalhealth.org/clinical-and-research-
programs/pregnancyregistry.
…
PATIENT COUNSELING INFORMATION
(Additions
underlined)
…
Use
in Specific Populations
Pregnancy
?
Advise pregnant women to notify their healthcare provider if they become
pregnant or intend to become pregnant during treatment with SYMBYAX. Advise
patients that SYMBYAX use later in pregnancy may lead to extrapyramidal
symptoms (tremors, abnormal muscle movements), an increased risk for neonatal
complications requiring prolonged hospitalization, respiratory distress, tube
feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Advise
patients that there is a pregnancy exposure registry that monitors pregnancy
outcomes in women exposed to SYMBYAX during pregnancy [see Use in Specific Populations (8.1)].
Lactation
? Advise breastfeeding women using SYMBYAX to monitor infants for agitation,
irritability, poor weight gain, poor feeding, excess sedation, and
extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek
medical care if they notice these signs. [see
Use in Specific Populations (8.2)].
Infertility
Advise
females of reproductive potential that SYMBYAX may impair fertility due to an
increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].
…
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or revisions underlined:
5.21 Anticholinergic (antimuscarinic) Effects
… Such adverse
reactions were not often the basis for study discontinuations; SYMBYAX should
be used with caution in patients with a current diagnosis or prior history
of urinary retention, clinically
significant prostatic hypertrophy, constipation, a history of paralytic ileus,
or related conditions …
6
Adverse Reactions
Newly added to the bulleted line listing:
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
… In
placebo-controlled studies of olanzapine in elderly patients with
dementia-related psychosis, there was a higher incidence of cerebrovascular
adverse events (e.g., stroke, transient ischemic attack) in patients treated
with olanzapine compared to patients treated with placebo. In 5
placebo-controlled studies of olanzapine in elderly patients with
dementia-related psychosis (n=1184), the following adverse reactions were
reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated
patients: falls, somnolence, peripheral edema, abnormal gait, urinary
incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry
mouth and visual hallucinations. The rate of discontinuation due to adverse
reactions was greater with olanzapine than placebo (13% vs 7%). Elderly
patients with dementia-related psychosis treated with olanzapine are at an
increased risk of death compared to placebo. Olanzapine is not approved for the
treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient
Counseling Information (17)]. Olanzapine is not approved for the
treatment of patients with dementia-related psychosis. Also, the presence of
factors that might decrease pharmacokinetic clearance …
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Serotonin Syndrome
Additions
and/or revisions underlined:
The development of a potentially
life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including
SYMBYAX, 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
…
If concomitant use of SYMBYAX with other
serotonergic drugs including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, buspirone, tryptophan, amphetamines, 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)
MEDICATION GUIDE
Addition
underlined:
Before
starting SYMBYAX, tell your doctor about all the medicines that you take, including:
PATIENT COUNSELING INFORMATION
17.9
Serotonin Syndrome
Additions
and/or revisions underlined:
Patients should be cautioned about the
risk of serotonin syndrome with the concomitant use of SYMBYAX and other
serotonergic agents including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s
Wort …
Approved Drug Label (PDF)
5
Warnings and Precautions
5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction
with Eosinophilia and Systemic Symptoms (DRESS) has been reported with
olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash
or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with
systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis,
and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS
is suspected.
6
Adverse Reactions
6.4 Postmarketing Experience
Adverse
reactions reported since market introduction that were temporally (but not
necessarily causally) related to SYMBYAX therapy include the following:
Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS) (addition underlined and added to paragraph
in alphabetical order)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
What are the possible side effects
of SYMBYAX
Serious side effects may happen when
you take SYMBYAX, including:
Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS): DRESS can
occur with SYMBYAX.
Features of DRESS may include rash, fever, swollen glands and other internal
organ involvement such as liver, kidney, lung and heart. DRESS is sometimes
fatal; therefore, tell your doctor immediately if you experience any of these
signs.
PATIENT COUNSELING INFORMATION
17.4 Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS)
Patients should
be advised to report to their health care provider at the earliest onset of any
signs and symptoms that may be associated with Drug Reaction with Eosinophilia
and Systemic Symptoms (DRESS).
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