`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat
`
`
`
`
`
`
` psychiatric disorders with PRISTIQ or within 7 days of stopping
` treatment with PRISTIQ. Do not use PRISTIQ within 14 days of
`
`
`
`stopping an MAOI intended to treat psychiatric disorders. In addition, do
`
`
`
`
`
`
` not start PRISTIQ in a patient who is being treated with linezolid or
` intravenous methylene blue (4).
`
`
`
` --------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
` • Serotonin Syndrome: Increased risk when co-administered with other
`
`
`
`
` serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken
`
` alone. If it occurs, discontinue PRISTIQ and initiate supportive treatment
`
`
` (5.2).
`
` • Elevated Blood Pressure: Control hypertension before initiating
`
`
`
`
`
` treatment. Monitor blood pressure regularly during treatment (5.3).
`
`
` • Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other
`
` antiplatelet drugs, warfarin, and other anticoagulants may increase this
`
`
`
`
` risk (5.4).
`
` • Angle Closure Glaucoma: Avoid use of antidepressants, including
`
`
` PRISTIQ, in patients with untreated anatomically narrow angles treated
`
` (5.5).
`
` • Activation of Mania/Hypomania: Use cautiously in patients with Bipolar
`
`
`
` Disorder. Caution patients about risk of activation of mania/hypomania
`
`(5.6).
`
` • Discontinuation Syndrome: Taper dose when possible and monitor for
`
`
`discontinuation symptoms (5.7).
`
` • Seizure: Can occur. Use cautiously in patients with seizure disorder
`
`
`(5.8).
`
`
` • Hyponatremia: Can occur in association with SIADH (5.9).
`
`
` • Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur (5.10).
`
`
` • Sexual Dysfunction: PRISTIQ may cause symptoms of sexual
`
`
`
`
`
` dysfunction (5.11).
`
`---------------------------- ADVERSE REACTIONS -----------------------------­
`
`
`
`
`Most common adverse reactions (incidence ≥5% and twice the rate of
`
`
`
`
`placebo in the 50 or 100 mg dose groups) were: nausea, dizziness,
`
`
`
`insomnia, hyperhidrosis, constipation, somnolence, decreased appetite,
`
`anxiety, and specific male sexual function disorders (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Wyeth
`
`Pharmaceuticals LLC, a subsidiary of Pfizer Inc., at 1-800-438-1985 or
`
`
`
`
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`--------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`
`
`
`
` • Pregnancy: Third trimester use may result in neonatal discontinuation
`
`
`
` syndrome (8.1).
`
`
`
`• Geriatric Use: There is an increased incidence of orthostatic hypotension
`
`
`
`
`
`
`in desvenlafaxine treated patients ≥ 65 years (6.1 and 8.5).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`Revised: 9/2021
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`PRISTIQ safely and effectively. See full prescribing information for
`
`PRISTIQ.
`
`PRISTIQ® (desvenlafaxine) Extended-Release Tablets, for oral use
`
`
`
`
`
`Initial U.S. Approval: 2008
`
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`Increased the risk of suicidal thoughts and behaviors in children,
`
`
`
`
`adolescents and young adults taking antidepressants (5.1).
`
`
`Closely monitor for clinical worsening and emergence of suicidal
`
`
`thoughts and behaviors (5.1).
`
`PRISTIQ is not approved for use in pediatric patients (8.4).
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`-------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`Warnings and Precautions, Sexual Dysfunction (5.11)
`9/2021
`
`
`
`
`
`------------------------- INDICATIONS AND USAGE---------------------------­
`
`
`PRISTIQ is a serotonin and norepinephrine reuptake inhibitor (SNRI)
`
`
`
`
`indicated for the treatment of adults with major depressive disorder (MDD)
`
`(1).
`
`
`
`
`
`
`---------------------DOSAGE AND ADMINISTRATION ----------------------­
`
` • Recommended dose: 50 mg once daily with or without food (2.1).
`
`
`
` • There was no evidence that doses greater than 50 mg per day confer any
`
`
`
` additional benefit (2.1).
`
` • The 25 mg per day dose is intended for a gradual reduction in dose when
`
`
`discontinuing treatment or dosing in severe renal and end-stage renal
`
`disease patients (2.1).
`
`
` • Discontinuation: Reduce dose gradually whenever possible (2.1).
`
`
`
`
` • Take tablets whole; do not divide, crush, chew, or dissolve (2.1).
`
` • Moderate renal impairment: Maximum dose 50 mg per day (2.2).
`
`
`
`
`
`
`
` • Severe renal impairment and end-stage renal disease: Maximum dose
`
`
`
`
`
`
` 25 mg per day or 50 mg every other day (2.2).
`
` • Moderate to severe hepatic impairment: Maximum dose 100 mg per day
`
`(2.3).
`
`
`
`
`
`
` ------------------- DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`
` • PRISTIQ extended-release tablets: 25 mg, 50 mg and 100 mg (3).
`
`
`
`
`
`
`
`
`
` • Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine
`
`
`
`
`
`
` succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine,
`
`
`
`
`
`
`
`
` respectively (3).
`
` ---------------------------- CONTRAINDICATIONS -----------------------------­
`
`
`
`
`• Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride
`
`or any excipients in the PRISTIQ formulation (4).
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4859709
`
`
`
` 1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Instructions for Use
`
`
`
`2.2 Dosage Recommendations for Patients with Renal Impairment
`
`
`2.3 Dosage Recommendations for Patients with Hepatic Impairment
`
`
`2.4 Maintenance/Continuation/Extended Treatment
`
`
`
`2.5 Discontinuing PRISTIQ
`
`
`
`2.6 Switching Patients From Other Antidepressants to PRISTIQ
`
`
`
`
`
`2.7 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI)
`
`
`
`
`
`
`
`Intended to Treat Psychiatric Disorders
`
`
`2.8 Use of PRISTIQ with other MAOIs such as Linezolid or Methylene
`
`
`Blue
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult
`
`
`
`
`Patients
`
`
`5.2 Serotonin Syndrome
`
`
`5.3 Elevated Blood Pressure
`
`
`5.4 Increased Risk of Bleeding
`
`
`
`
`5.5 Angle Closure Glaucoma
`
`
`5.6 Activation of Mania/Hypomania
`
`
`
`5.7 Discontinuation Syndrome
`
`
`
`
`5.8 Seizure
`
`
`
`5.9 Hyponatremia
`
`
`
`5.10 Interstitial Lung Disease and Eosinophilic Pneumonia
`
`
`
`5.11 Sexual Dysfunction
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`
`6.2 Postmarketing Experience
`
`
`
`
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`7.1 Drugs Having Clinically Important Interactions with PRISTIQ
`
`
`
`7.2 Drugs Having No Clinically Important Interactions with PRISTIQ
`
`
`
`
`7.3 Alcohol
`
`
`
`7.4 Drug-Laboratory Test Interactions
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`8.7 Hepatic Impairment
`
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`
`10 OVERDOSAGE
`
`10.1 Human Experience with Overdosage
`
`
`
`10.2 Management of Overdosage
`
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the full prescribing information are
`
`not listed.
`
`
`
`
`
`
`
`
`Reference ID: 4859709
`
`
`
` 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`
`
` Antidepressants increased the risk of suicidal thoughts and behavior in children,
`
` adolescents, and young adults in short-term studies. These studies did not show an
`
`
`
`
` increase in the risk of suicidal thoughts and behavior with antidepressant use in patients
`
`
`
`
`
` over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and
`
`
`
`
`
`
` older [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`In patients of all ages who are started on antidepressant therapy, monitor closely for
`
`
`worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
`
`
`caregivers of the need for close observation and communication with the prescriber [see
`
`Warnings and Precautions (5.1)].
`
`PRISTIQ is not approved for use in pediatric patients [see Use in Specific Populations
`(8.4)].
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
`1
`
` PRISTIQ is indicated for the treatment of adults with major depressive disorder (MDD) [see
`
` Clinical Studies (14)].
`
`2
`
` 2.1 General Instructions for Use
`
` The recommended dose for PRISTIQ is 50 mg once daily, with or without food. The 50 mg
`
`
`
`
` dose is both a starting dose and the therapeutic dose. PRISTIQ should be taken at
` approximately the same time each day. Tablets must be swallowed whole with fluid and not
`
`
`
` divided, crushed, chewed, or dissolved.
`
`In clinical studies, doses of 10 mg to 400 mg per day were studied. In clinical studies, doses of
`
`
`
`
`
`
`50 mg to 400 mg per day were shown to be effective, although no additional benefit was
`
`
`
`
`
`
`demonstrated at doses greater than 50 mg per day and adverse reactions and discontinuations
`
`
`
`
`
`were more frequent at higher doses.
`
`
`
`The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing
`
`
`
`
`
`
`treatment. When discontinuing therapy, gradual dose reduction is recommended whenever
`
`
`possible to minimize discontinuation symptoms [see Dosage and Administration (2.5) and
`
`
`
`Warnings and Precautions (5.7)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4859709
`
`
`
` 3
`
`
`

`

`
`
`
`
`
`
` 2.2 Dosage Recommendations for Patients with Renal Impairment
`
`
`
`
`
`The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine
`
`
`
`
`
`
`
`
`clearance [ClCr] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum
`
`
`
`
` recommended dose in patients with severe renal impairment (ClCr 15 to 29 mL/min, C-G) or
`
`
` end-stage renal disease (ESRD, ClCr < 15 mL/min, C-G) is 25 mg every day or 50 mg every
`
`
`
`
`
`
`
`
`
`other day. Supplemental doses should not be given to patients after dialysis [see Use in Specific
`
`Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`2.3 Dosage Recommendations for Patients with Hepatic Impairment
`
`
`
`The recommended dose in patients with moderate to severe hepatic impairment (Child-Pugh
`
`
`
`
`
`
`
`score 7 to 15) is 50 mg per day. Dose escalation above 100 mg per day is not recommended
`
`[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
`
`
`
`2.4 Maintenance/Continuation/Extended Treatment
`
`
`
`
`It is generally agreed that acute episodes of major depressive disorder require several months or
`
`
`longer of sustained pharmacologic therapy. Longer-term efficacy of PRISTIQ (50-400 mg) was
`
`
`
`
`
`established in two maintenance trials [see Clinical Studies (14)]. Patients should be
`
`
`
`periodically reassessed to determine the need for continued treatment.
`
`
`
`2.5 Discontinuing PRISTIQ
`
`
`
`
`Adverse reactions may occur upon discontinuation of PRISTIQ [see Warnings and Precautions
`
`
`
`
`
`(5.7)]. Gradually reduce the dosage rather than stopping PRISTIQ abruptly whenever possible.
`
`
`2.6
`
`
`Discontinuation symptoms have been reported when switching patients from other
`
`antidepressants, including venlafaxine, to PRISTIQ. Tapering of the initial antidepressant may
`
`be necessary to minimize discontinuation symptoms.
`
`
`
`
`
`
`Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to
`2.7
`
`Treat Psychiatric Disorders
`
`
`
`At least 14 days should elapse between discontinuation of an MAOI intended to treat
`
`
`
`
`psychiatric disorders and initiation of therapy with PRISTIQ. Conversely, at least 7 days
`
`should be allowed after stopping PRISTIQ before starting an MAOI intended to treat
`
`
`psychiatric disorders [see Contraindications (4)].
`
`
`
`
`
`2.8 Use of PRISTIQ with other MAOIs such as Linezolid or Methylene Blue
`
`
`
`
`
`
`Do not start PRISTIQ in a patient who is being treated with linezolid or intravenous methylene
`
`blue because there is increased risk of serotonin syndrome. In a patient who requires more
`
`
`
`
`Switching Patients From Other Antidepressants to PRISTIQ
`
`
`Reference ID: 4859709
`
`
`
` 4
`
`
`

`

` urgent treatment of a psychiatric condition, other interventions, including hospitalization,
`
`
`
`
`
` should be considered [see Contraindications (4)].
`
`
`
`
`
`
`
`
`In some cases, a patient already receiving PRISTIQ therapy may require urgent treatment with
`
`
`
`
`linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous
`
`methylene blue treatment are not available and the potential benefits of linezolid or intravenous
`
`
`
`
`methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular
`
`
`
`patient, PRISTIQ should be stopped promptly, and linezolid or intravenous methylene blue can
`
`be administered. The patient should be monitored for symptoms of serotonin syndrome for
`
`
`
`
`
`
`
`7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue,
`
`
`
`
`
`whichever comes first. Therapy with PRISTIQ may be resumed 24 hours after the last dose of
`
`
`
`
`
`
`linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by
`
`
`
`
`local injection) or in intravenous doses much lower than 1 mg/kg with PRISTIQ is unclear. The
`
`
`
`clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin
`
`
`
`
`syndrome with such use [see Warnings and Precautions (5.2)].
`
`
`
`
`3
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`
`• 25 mg Tablet: tan, square pyramid tablet debossed with “W” over “25” on the flat
`
`side
`
`
`
`
`
`
`• 50 mg Tablet: light pink, square pyramid tablet debossed with “W” over “50” on the
`
`flat side
`
`
`
`
`
`
`• 100 mg Tablet: reddish-orange, square pyramid tablet debossed with “W” over
`
`
`“100” on the flat side
`
`
`CONTRAINDICATIONS
`
`
`
`• Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any
`
`
`excipients in the PRISTIQ formulation. Angioedema has been reported in patients
`
`
`
`treated with PRISTIQ [see Adverse Reactions (6.1)].
`
`
`
`
`
`
`• The use of MAOIs intended to treat psychiatric disorders with PRISTIQ or within
`
`
`
`7 days of stopping treatment with PRISTIQ is contraindicated because of an
`
`
`
`
`increased risk of serotonin syndrome. The use of PRISTIQ within 14 days of
`
`
`
`
`
`stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see
`
`
`
`
`Dosage and Administration (2.7) and Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`• Starting PRISTIQ in a patient who is being treated with MAOIs such as linezolid or
`
`
`
`intravenous methylene blue is also contraindicated because of an increased risk of
`
`serotonin syndrome [see Dosage and Administration (2.8) and Warnings and
`
`
`
`
`
`
`
`Precautions (5.2)].
`
`
`
`4
`
`
`
`
`
`
`
`
`
`Reference ID: 4859709
`
`
`
` 5
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`5.1
`
`Patients with MDD, both adult and pediatric, may experience worsening of their depression
`
`and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in
`
`
`behavior, whether or not they are taking antidepressant medications, and this risk may persist
`
`
`
`until significant remission occurs. Suicide is a known risk of depression and certain other
`
`
`
`psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
`There has been a long-standing concern, however, that antidepressants may have a role in
`
` inducing worsening of depression and the emergence of suicidality in certain patients during
` the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of
`
`
`
` antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal
`
` thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24)
`
`
`
` with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did
`
`
`not show an increase in the risk of suicidality with antidepressants compared to placebo in
`
` adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults
` aged 65 and older.
`
`
`
`The pooled analyses of placebo-controlled studies in children and adolescents with MDD,
`
`
` obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
` 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
`
`
`
`
` placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of
` 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over
`
`
`
`
`
`
` 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a
` tendency toward an increase in the younger patients for almost all drugs studied. There were
`
`
`
` differences in absolute risk of suicidality across the different indications, with the highest
` incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable
`
`within age strata and across indications. These risk differences (drug-placebo difference in the
`
`
`
` number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
`
`
`
`
`
` No suicides occurred in any of the pediatric studies. There were suicides in the adult studies,
`
` but the number was not sufficient to reach any conclusion about drug effect on suicide.
`
`
`
`
`
`
`Reference ID: 4859709
`
`
`
` 6
`
`
`
`
`
`
`
`Table 1
`
` Drug-Placebo Difference in Number of Cases of Suicidality per 1,000
`
` Patients Treated
` Increases Compared to Placebo
`
` 14 additional cases
`
`
` 5 additional cases
` Decreases Compared to Placebo
`
` 1 fewer case
`6 fewer cases
`
`
`
`
`
`
`
`
` Age Range
`
`<18
`
`
` 18 to 24
`
` 25 to 64
`
`
` ≥65
`
`

`

`
`
`
`
` It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
`
`
`
`
` months. However, there is substantial evidence from placebo-controlled maintenance studies in
` adults with depression that the use of antidepressants can delay the recurrence of depression.
`
`
`
`All patients being treated with antidepressants for any indication should be monitored
`appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
`
`
`
` behavior, especially during the initial few months of a course of drug therapy, or at times of
`
` dose changes, either increases or decreases.
`
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
` aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
`been reported in adult and pediatric patients being treated with antidepressants for major
`depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
`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.
`
`
`
`
`Consideration should be given to changing the therapeutic regimen, including possibly
`
`
`
`discontinuing the medication, in patients whose depression is persistently worse, or who are
`
`experiencing 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 symptoms.
`
`
`If the decision has been made to discontinue treatment, medication should be tapered, as
`
`
`rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
`
`
`certain symptoms [see Dosage and Administration (2.4), Warnings and Precautions (5.7)].
`
`
`
`
`Families and caregivers of patients being treated with antidepressants for major depressive
`
`
`disorder or other indications, both psychiatric and nonpsychiatric, 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. Such monitoring should include
`
`
`daily observation by families and caregivers.
`
`
`Prescriptions for PRISTIQ should be written for the smallest quantity of tablets consistent with
`
`good patient management, in order to reduce the risk of overdose.
`
`
`
`Screening Patients for Bipolar Disorder
`
`
`A major depressive episode may be the initial presentation of bipolar disorder. It is generally
`
`
`believed (though not established in controlled studies) that treating such an episode with an
`
`
`antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in
`
`
`
`
`patients at risk for bipolar disorder. Whether any of the symptoms described above represent
`
`such a conversion is unknown. However, prior to initiating treatment with an antidepressant,
`patients with depressive symptoms should be adequately screened to determine if they are at
`
`
`risk for bipolar disorder; such screening should include a detailed psychiatric history, including
`
`
`
`Reference ID: 4859709
`
`
`
` 7
`
`
`

`

`
`Serotonin Syndrome
`
`
`
`
`
`
`
` a family history of suicide, bipolar disorder, and depression. It should be noted that PRISTIQ is
`
`
` not approved for use in treating bipolar depression.
`
`
`5.2
`
`
`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 [see Contraindications (4), Drug Interactions (7.1)]. 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), autonomic instability (e.g., tachycardia, labile blood
`
`pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g.,
`
`
`tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal
`
`symptoms (e.g., nausea, vomiting, diarrhea).
`
`
`
`
`
`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. 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 PRISTIQ, discontinue PRISTIQ
`
`
`
`before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].
`
`
`
`
`
`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.
`
`
`5.3 Elevated Blood Pressure
`
`
`
`Patients receiving PRISTIQ should have regular monitoring of blood pressure since increases
`
`in blood pressure were observed in clinical studies [see Adverse Reactions (6.1)]. Pre-existing
`
`
`
`hypertension should be controlled before initiating treatment with PRISTIQ. Caution should be
`
`
`
`exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular
`conditions that might be compromised by increases in blood pressure. Cases of elevated blood
`
`
`
`pressure requiring immediate treatment have been reported with PRISTIQ.
`
`
`Sustained blood pressure increases could have adverse consequences. For patients who
`experience a sustained increase in blood pressure while receiving PRISTIQ, either dose
`
`
`
`reduction or discontinuation should be considered [see Adverse Reactions (6.1)].
`
`
`Reference ID: 4859709
`
`
`
` 8
`
`
`

`

`
`
` Increased Risk of Bleeding
`
`
`
`
`5.4
`
`
`
`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. Bleeding
`
`
` events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and
` petechiae to life-threatening hemorrhages. 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
`
`
`
`The pupillary dilation that occurs following use of many antidepressant drugs including
`
`
`
`PRISTIQ may trigger an angle closure attack 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.
`
`
`
`
`5.6 Activation of Mania/Hypomania
`
`
`
`During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of
`
`patients treated with PRISTIQ. Activation of mania/hypomania has also been reported in a
`
`
`small proportion of patients with major affective disorder who were treated with other
`
`marketed antidepressants. As with all antidepressants, PRISTIQ should be used cautiously in
`
`patients with a history or family history of mania or hypomania.
`
`
`
`
`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 [see Dosage and Administration (2.5), Adverse Reactions (6.1)].
`
`
`
`
`Seizure
`
`
`
`5.8
`
`
`
`Cases of seizure have been reported in pre-marketing clinical studies with PRISTIQ. PRISTIQ
`
`
`has not been systematically evaluated in patients with a seizure disorder. Patients with a history
`of seizures were excluded from pre-marketing clinical studies. PRISTIQ should be prescribed
`
`
`with caution in patients with a seizure disorder.
`
`
`
`Reference ID: 4859709
`
`
`
` 9
`
`
`

`

`
`
`
`
`
`
`ADVERSE REACTIONS
`
`
`
`
`
`
` 5.9 Hyponatremia
`
`
`Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ.
`
`
`In many cases, this 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. Elderly patients may be at greater risk of developing hyponatremia with
`
`
`SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be
`
`at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
`
`Discontinuation of PRISTIQ should be considered in patients with symptomatic hyponatremia
`
`and appropriate medical intervention should be instituted.
`
`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, and death.
`
`
`
`
`5.10 Interstitial Lung Disease and Eosinophilic Pneumonia
`
`
`
`Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent
`
`drug of PRISTIQ) therapy have been rarely reported. The possibility of these adverse events
`
`should be considered in patients treated with PRISTIQ who present with progressive dyspnea,
`cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and
`
`
`discontinuation of PRISTIQ should be considered.
`
`
`5.11 Sexual Dysfunction
`
`
`
`Use of SNRIs, including PRISTIQ, may cause symptoms of sexual dysfunction [see Adverse
`
`Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure,
`decreased libido, and erectile dysfunction. In female patients, SNRI 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 PRISTIQ
`
`
`
`
`
`
`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.
`
`
`6
`
`The following adverse reactions are discussed in greater detail in other sections of the label.
`
`
`
`
` • Hypersensitivity [see Contraindications (4)]
`
`
` • Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [see Warnings
`
`
`
`
`
` and Precautions (5.1)]
`
` • Serotonin Syndrome [see Warnings and Precautions (5.2)]
`
`
`
`
`
`
`
`
`Reference ID: 4859709
`
`
`
` 10
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` • Elevated Blood Pressure [see Warnings and Precautions (5.3)]
`
`
` • Increased Risk of Bleeding [see Warnings and Precautions (5.4)]
`
`
` • Angle Closure Glaucoma [see Warnings and Precautions (5.5)]
`
`
`
`
` • Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]
`
`
`
` • Discontinuation Syndrome [see Warnings and Precautions (5.7)]
`
`
`
` • Seizure [see Warnings and Precautions (5.8)]
`
`
`
` • Hyponatremia [see Warnings and Precautions (5.9)]
`
`
`
` • Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions
`
`
`
`
` (5.10)]
`
` • Sexual Dysfunction [see Warnings and Precautions (5.11)]
`
`
`
`6.1 Clinical Studies Experience
`
`
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`
`
`
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`
`
`studies of another drug and may not reflect the rates observed in clinical practice.
`
`
`Patient Exposure
`
`
`
`
`
`PRISTIQ was evaluated for safety in 8,394 patients diagnosed with major depressive disorder
`
`
`who participated in multiple-dose pre-marketing studies, representing 2,784 patient-years of
`
`
`
`exposure. Of the total 8,394 patients exposed to at least one dose of PRISTIQ; 2,116 were
`
`
`
`
`exposed to PRISTIQ for 6 months, representing 1,658 patient-years of exposure, and 421 were
`
`
`
`exposed for one