`
`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, oral
`
`Initial U.S. Approval: 2008
`
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`See full prescribing information for complete boxed warning.
`
`
`
`Increased risk of suicidal thinking and behavior in children, adolescents
`
`
`and young adults taking antidepressants for major depressive disorder
`(MDD) and other psychiatric disorders. PRISTIQ is not approved for use
`in pediatric patients (5.1).
`
`
`December 2012
`
`
`----------------------------RECENT MAJOR CHANGES-------------------
`Dosage and Administration,
`
`December 2012
`Special Populations (2.2)
`
`Switching a Patient To or From a Monoamine Oxidase
`
`
`December 2012
`Inhibitor (MAOI) Antidepressant (2.6)
`
`
`Contraindications,
`Monoamine Oxidase Inhibitors (4.2)
`Warnings and Precautions,
`
`Serotonin Syndrome (5.2)
`December 2012
`
`———————— INDICATIONS AND USAGE ————————
`
`PRISTIQ, a selective serotonin and norepinephrine reuptake inhibitor
`
`(SNRI), is indicated for the treatment of 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/day confer
`any additional benefit (2.1).
`
`
` When discontinuing treatment, gradual dose reduction is
`
` recommended whenever possible (2.1 and 5.9).
`
`
` Tablets should be taken whole; do not divide, crush, chew, or
`
`
` dissolve (2.1).
`
`
` Renal Impairment: The recommended dose in patients with
`
`moderate renal impairment is 50 mg/day. The recommended dose
`in patients with severe renal impairment and end-stage renal
`disease (ESRD) is 50 mg every other day. The dose should not be
`
`
`
`escalated in patients with moderate or severe renal impairment or
`
`ESRD (2.2).
`
`
` Hepatic Impairment: Dose escalation above 100 mg/day is not
`
`
` recommended (2.2).
`
` —————— DOSAGE FORMS AND STRENGTHS ——————
`
` PRISTIQ tablets are available as 50 and 100 mg tablets (3).
`
`
`
` Each tablet contains 76 mg or 152 mg of desvenlafaxine succinate
`
`
`
` equivalent to 50 mg or 100 mg of desvenlafaxine (3).
`
`
`
`
`————————— CONTRAINDICATIONS ————————
`
` Hypersensitivity to desvenlafaxine succinate, venlafaxine
`
` hydrochloride or any excipients in the PRISTIQ formulation
`
`
`
` (4.1).
`
` 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 (4.2).
`
`
`——————— WARNINGS AND PRECAUTIONS ——————
`
`
`
` Clinical Worsening/Suicide Risk: Monitor for clinical
`
`
` worsening and suicide risk (5.1).
`
` Serotonin Syndrome: Serotonin syndrome has been reported
`
`with SSRIs and SNRIs, including with PRISTIQ, both when
`taken alone, but especially when co-administered with other
`
`
`
`
`Reference ID: 3227645
`
`1
`
`
`
`
`
`
` serotonergic agents (including triptans, tricyclic antidepressants,
`
` fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's
`
` Wort). If such symptoms occur, discontinue PRISTIQ and initiate
`
` supportive treatment. If concomitant use of PRISTIQ with other
`
`
`serotonergic drugs is clinically warranted, patients should be
`
`made aware of a potential increased risk for serotonin syndrome,
`
`particularly during treatment initiation and dose increases (5.2).
`
` Elevated Blood Pressure: Has occurred with PRISTIQ.
`
`
`Hypertension should be controlled before initiating treatment.
`
`
`Monitor blood pressure regularly during treatment (5.3).
`
` Abnormal Bleeding: PRISTIQ may increase the risk of bleeding
`
`events. Patients should be cautioned about the risk of bleeding
`
`associated with the concomitant use of PRISTIQ and NSAIDs,
`
`aspirin, or other drugs that affect coagulation (5.4).
`
` Narrow-angle Glaucoma: Mydriasis has occurred with
`
` PRISTIQ. Patients with raised intraocular pressure or those at risk
`
` of angle-closure glaucoma should be monitored (5.5).
`
` Activation of Mania/Hypomania: Has occurred. Use cautiously
`
`
` in patients with Bipolar Disorder. Caution patients about the risk
`
`
` of activation of mania/hypomania (5.6).
`
` Cardiovascular/Cerebrovascular Disease: Use cautiously in
`
`
` patients with cardiovascular or cerebrovascular disease (5.7).
`
`
` Cholesterol and Triglyceride Elevation: Have occurred. Use
`
`
`cautiously in patients with lipid metabolism disorders. Consider
`
`
`
`monitoring serum cholesterol and triglyceride (5.8).
`
` Discontinuation Symptoms: Have occurred. Taper the dose
`when possible and monitor for discontinuation symptoms (5.9).
`
`
` Renal Impairment: Reduces the clearance of PRISTIQ. Dosage
`
`
`adjustment is necessary in severe and ESRD. In moderate renal
`
`impairment, the dose should not exceed 50 mg/day (5.10).
`
` Seizure: Can occur. Use cautiously in patients with seizure
`
`
`disorder (5.11).
`
` Hyponatremia: Can occur in association with SIADH (5.12).
`
`
` Drugs Containing Desvenlafaxine or Venlafaxine: Should not
`
`
` be used concomitantly with PRISTIQ (5.13).
` Interstitial Lung Disease and Eosinophilic Pneumonia: Can
`
` occur (5.14).
` ————————— ADVERSE REACTIONS —————————
`
`Adverse reactions in patients in short-term fixed-dose studies (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 Inc., a subsidiary of Pfizer Inc., at 1-800-934-5556 or
`
` FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`
` ——————— USE IN SPECIFIC POPULATIONS ——————
`
`
` Dosage adjustment is recommended in patients with severe renal
`
`
` impairment and end-stage renal disease. The dose should not be
` escalated in moderate to severe impairment or in ESRD (2.2, 8.6
`
`
`
`
` and 12.6).
`
` There is an increased incidence of orthostatic hypotension in
`
` PRISTIQ treated patients ≥ 65 years (6.1 and 8.5).
`
`
`
` For elderly patients, the possibility of reduced renal clearance of
`
` desvenlafaxine should be considered when determining dose
`
`
`
`
` (2.2).
`
` Only administer PRISTIQ to pregnant or breastfeeding women if
`
`the expected benefits outweigh the possible risks (8.1 and 8.3).
`See 17 for PATIENT COUNSELING INFORMATION and the
`
`FDA-approved Medication Guide.
`
`
`
`
`
`
`Revised: 12/2012
`
`
`
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS *
`
`
`
`
`
`
`
`
`
`
` WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
` 1 INDICATIONS AND USAGE
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` 2.1 Initial Treatment of Major Depressive Disorder
`
`
` 2.2 Special Populations
`
` 2.3 Maintenance/Continuation/Extended Treatment
`
`
` 2.4 Discontinuing PRISTIQ
`
` 2.5 Switching Patients From Other Antidepressants to PRISTIQ
`
`
`
` 2.6 Switching a Patient To or From a Monoamine Oxidase Inhibitor
`
`(MAOI) Intended to Treat Psychiatric Disorders
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`4.1 Hypersensitivity
`
`
`4.2 Monoamine Oxidase Inhibitors
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Clinical Worsening and Suicide Risk
`
`
`5.2 Serotonin Syndrome
`
`5.3 Elevated Blood Pressure
`
`5.4 Abnormal Bleeding
`
`
`5.5 Narrow-angle Glaucoma
`
`
`
`5.6 Activation of Mania/Hypomania
`
`
`5.7 Cardiovascular/Cerebrovascular Disease
`
`5.8 Serum Cholesterol and Triglyceride Elevation
`
`5.9 Discontinuation of Treatment with PRISTIQ
`
`
`5.10 Renal Impairment
`
`
`5.11 Seizure
`
`5.12 Hyponatremia
`
`5.13 Co-administration of Drugs Containing Desvenlafaxine and
`
`Venlafaxine
`
`
`5.14 Interstitial Lung Disease and Eosinophilic Pneumonia
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`6.2 Adverse Reactions Identified During Post-Approval Use
`
`6.3 Adverse Reactions Reported With Other SNRIs
`
`7 DRUG INTERACTIONS
`
`7.1 Central Nervous System (CNS)-Active Agents
`
`
`7.2 Monoamine Oxidase Inhibitors (MAOI)
`
`
`7.3 Serotonergic Drugs
`
`
`7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and
`
`
`Warfarin)
`
`7.5 Ethanol
`
`
`7.6 Potential for Other Drugs to Affect Desvenlafaxine
`
`7.7 Potential for Desvenlafaxine to Affect Other Drugs
`
`
`7.8 P-glycoprotein Transporter
`
`7.9 Electroconvulsive Therapy
`
`
`
`
`
`
`
`7.10 Drug-Laboratory Test Interactions
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`
`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
`
`
`9.2 Abuse and Dependence
`
`
`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
`
`
`12.4 Absorption and Distribution
`
`
`12.5 Metabolism and Elimination
`
`
`12.6 Special Populations
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Suicide Risk
`
`
`17.2 Concomitant Medication
`
`
`
`17.3 Serotonin Syndrome
`
`
`17.4 Elevated Blood Pressure
`
`
`17.5 Abnormal Bleeding
`
`
`17.6 Narrow-angle Glaucoma
`
`
`17.7 Activation of Mania/Hypomania
`
`
`17.8 Cardiovascular/Cerebrovascular Disease
`
`
`17.9 Serum Cholesterol and Triglyceride Elevation
`
`
`17.10 Discontinuation
`
`
`17.11 Switching Patients From Other Antidepressants to PRISTIQ
`
`
`17.12 Interference with Cognitive and Motor Performance
`
`
`17.13 Alcohol
`
`
`17.14 Allergic Reactions
`
`
`17.15 Pregnancy
`
`
`17.16 Nursing
`
`
`17.17 Residual Inert Matrix Tablet
`
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`Reference ID: 3227645
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
`
` (suicidality) in children, adolescents, and young adults in short-term studies of Major
`
` Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of
`PRISTIQ® or any other antidepressant in a child, adolescent, or young adult must balance
`
`this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older.
`Depression and certain other psychiatric disorders are themselves associated with increases
`
` in the risk of suicide. Patients of all ages who are started on antidepressant therapy should
` be monitored appropriately and observed closely for clinical worsening, suicidality, or
`
`unusual changes in behavior. Families and caregivers should be advised of the need for
`close observation and communication with the prescriber. PRISTIQ is not approved for
`use in pediatric patients [see Warnings and Precautions (5.1), Use in Specific Populations
`(8.4), and Patient Counseling Information (17.1)].
`
`
`1 INDICATIONS AND USAGE
`
`
`PRISTIQ, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for
`the treatment of major depressive disorder (MDD) [see Clinical Studies (14) and Dosage and
`Administration (2.1)]. The efficacy of PRISTIQ has been established in four 8-week, placebo-
`controlled studies of outpatients who met DSM-IV criteria for major depressive disorder.
`
`A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly
`
`
`every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily
`
`
`functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of
`interest in usual activities, significant change in weight and/or appetite, insomnia or
`hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or
`worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal
`ideation.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Initial Treatment of Major Depressive Disorder
`
`
`The recommended dose for PRISTIQ is 50 mg once daily, with or without food.
`
`In clinical studies, doses of 50-400 mg/day were shown to be effective, although no additional
`benefit was demonstrated at doses greater than 50 mg/day and adverse events and
`discontinuations were more frequent at higher doses.
`
`
`Reference ID: 3227645
`
`3
`
`
`

`

`
`
`When discontinuing therapy, gradual dose reduction is recommended whenever possible to
`minimize discontinuation symptoms [see Dosage and Administration (2.4) and Warnings and
`Precautions (5.9)].
`
`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.
`
`2.2 Special Populations
`
`
`
` Pregnant women during the third trimester
`
`Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications
`requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific
`Populations (8.1)]. When treating pregnant women with PRISTIQ during the third trimester,
`the physician should carefully consider the potential risks and benefits of treatment.
`
`Patients with renal impairment
`
`
`No dosage adjustment is necessary in patients with mild renal impairment (24-hr CrCl = 50­
`80 mL/min).
`
`The recommended dose in patients with moderate renal impairment (24-hr CrCl = 30­
`
` 50 mL/min) is 50 mg per day. The recommended dose in patients with severe renal impairment
` (24-hr CrCl < 30 mL/min) or end-stage renal disease (ESRD) is 50 mg every other day.
`
`Supplemental doses should not be given to patients after dialysis. The doses should not be
`escalated in patients with moderate or severe renal impairment, or ESRD [see Warnings and
`Precautions (5.10), Use in Specific Populations (8.6) and Clinical Pharmacology (12.6)].
`
`
`
` Patients with hepatic impairment
`
`The recommended dose in patients with hepatic impairment is 50 mg/day. Dose escalation
`above 100 mg/day is not recommended [see Clinical Pharmacology (12.6)].
`
`
`Elderly patients
`
`No dosage adjustment is required solely on the basis of age; however, the possibility of reduced
`
`renal clearance of PRISTIQ should be considered when determining the dose [see Use in
`Specific Populations (8.5) and Clinical Pharmacology (12.6)].
`
`2.3 Maintenance/Continuation/Extended Treatment
`
`It is generally agreed that acute episodes of major depressive disorder require several months or
`longer of sustained pharmacologic therapy. However, the longer-term efficacy of PRISTIQ at a
`dose of 50 mg/day that was effective in short-term, controlled studies has not been studied.
`Patients should be periodically reassessed to determine the need for continued treatment.
`
`
`Reference ID: 3227645
`
`4
`
`
`

`

`
`
`2.4 Discontinuing PRISTIQ
`
`Symptoms associated with discontinuation of PRISTIQ, other SNRIs and SSRIs have been
`reported [see Warnings and Precautions (5.9)]. Patients should be monitored for these
`symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt
`cessation is recommended whenever possible. If intolerable symptoms occur following a
`decrease in the dose or upon discontinuation of treatment, then resuming the previously
`
`prescribed dose may be considered. Subsequently, the physician may continue decreasing the
`dose, but at a more gradual rate.
`
`2.5 Switching Patients From Other Antidepressants to PRISTIQ
`
`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 [see Contraindications (4.2)].
`
`2.6 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to
`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)].
`
`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
`urgent treatment of a psychiatric condition, other interventions, including hospitalization,
`should be considered [see Contraindications (4.2)].
`
`
`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)].
`
`
`
`
`Reference ID: 3227645
`
`5
`
`
`

`

`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`PRISTIQ® (desvenlafaxine) Extended-Release Tablets are available as 50 and 100 mg tablets.
`
`50 mg, light pink, square pyramid tablet debossed with “W” over “50” on the flat side
`
`100 mg, reddish-orange, square pyramid tablet debossed with “W” over “100” on the flat side
`
`4 CONTRAINDICATIONS
`
`4.1 Hypersensitivity
`
`Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in
`the PRISTIQ formulation.
`
`4.2 Monoamine Oxidase Inhibitors
`
`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 (2.6) 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 (2.6) and Warnings and Precautions (5.2)].
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Clinical Worsening and Suicide Risk
`
`Patients with major depressive disorder (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 18-24) 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
`
`
`Reference ID: 3227645
`
`6
`
`
`

`

`
`
`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 1000 patients treated) are provided in Table 1.
`
`Table 1
`
`Drug-Placebo Difference in Number of Cases of Suicidality per 1000 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
`18-24
`
`25-64
`≥65
`
`
`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.
`
`
`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.
`
`
`Reference ID: 3227645
`
`7
`
`
`

`

`
`
`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 Warnings and Precautions (5.9) and Dosage and Administration (2.3)
`
`for a description of the risks of discontinuation of PRISTIQ].
`
`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
`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 Syndrome
`
`
`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, 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).
`
`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), seizures, and/or gastrointestinal
`symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of
`serotonin syndrome.
`
`The concomitant use of PRISTIQ with MAOIs intended to treat psychiatric disorders is
`contraindicated. PRISTIQ should also not be started 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
`
`
`
`Reference ID: 3227645
`
`8
`
`
`

`

`
`
`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 a MAOI such as linezolid or
`intravenous methylene blue in a patient taking PRISTIQ. PRISTIQ should be discontinued
`before initiating treatment with the MAOI [see Contraindications (4.2) and Dosage and
`
`
`
`Administration (2.6)].
`
`If concomitant use of PRISTIQ with other serotonergic drugs, including triptans, tricyclic
`antidepressants, fentanyl, lithium, tramadol, buspirone, 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.
`
`Treatment with PRISTIQ and any concomitant serotonergic agents should be discontinued
`
`immediately if the above events occur and supportive symptomatic treatment should be
`initiated.
`
`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. Pre-existing hypertension should be
`controlled before initiating treatment with PRISTIQ. Caution should be exercised in treating
`patients with pre-existing hypertension or other underlying conditions that might be
`compromised by increases in blood pressure. Cases of elevated blood pressure requiring
`immediate treatment have been reported with PRISTIQ.
`
`Sustained hypertension
`
`
`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)]. Treatment
`with PRISTIQ at all doses from 50 mg/day to 400 mg/day in controlled studies was associated
`with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure
`(SDBP) ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive on-therapy visits (see
`
`Table 2). Analyses of patients in PRISTIQ controlled studies who met criteria for sustained
`hypertension revealed a consistent increase in the proportion of patients who developed
`sustained hypertension. This was seen at all doses with a suggestion of a higher rate at
`400 mg/day.
`
`Table 2: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood
`
`
` Pressure
`
` Proportion of Patients with Sustained Hypertension
`0.5%
`1.3%
`0.7%
`1.1%
`2.3%
`
`
`
`
`
`Treatment Group
`Placebo
` PRISTIQ 50 mg/day
`
`
` PRISTIQ 100 mg/day
`
` PRISTIQ 200 mg/day
`
` PRISTIQ 400 mg/day
`
`
`
`Reference ID: 3227645
`
`9
`
`
`

`

`
`
`5.4 Abnormal Bleeding
`
`
` SSRIs and SNRIs, 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.
`Patients should be cautioned about the risk of bleeding associated with the concomitant use of
`PRISTIQ and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
`
`5.5 Narrow-angle Glaucoma
`
`Mydriasis has been reported in association with PRISTIQ; therefore, patients with raised
`intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma)
`should be monitored.
`
`5.6 Activation of Mania/Hypomania
`
`During all MDD and VMS (vasomotor symptoms) phase 2 and phase 3 studies, mania was
`reported for approximately 0.1% 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 Cardiovascular/Cerebrovascular Disease
`
`
`Caution is advised in administering PRISTIQ to patients with cardiovascular, cerebrovascular,
`or lipid metabolism disorders [see Adverse Reactions (6.1)]. Increases in blood pressure and
`small increases in heart rate were observed in clinical studies with PRISTIQ. PRISTIQ has not
`been evaluated systematically in patients with a recent history of myocardial infarction,
`unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with
`these diagnoses, except for cerebrovascular disease, were excluded from clinical studies.
`
`5.8 Serum Cholesterol and Triglyceride Elevation
`
`Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein)
`cholesterol, and triglycerides were observed in the controlled studies. Measurement of serum
`
`l