` 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 serotonergic agents
`
`
`
`
`
`
`
`
` (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,
`
`
`
`
`
`
` tryptophan, buspirone, amphetamines, 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: Control hypertension before
`
`
`
` initiating
`
`
`
`
`
` treatment. Monitor blood pressure regularly during treatment (5.3).
`
`
`
`
`
`
`
`
` Abnormal Bleeding: PRISTIQ may increase risk of bleeding events.
`
`
`
`
`
`
`
`
`
`
` Caution patients about risk of bleeding associated with concomitant use
`
`
`
`
`
`
`
`
`
` of PRISTIQ and NSAIDs, aspirin, or other drugs that affect coagulation
`
`
`
`
`
`
`
`
` (5.4).
`
`
` Angle Closure Glaucoma: Angle closure glaucoma has occurred in
`
`
`
`
`
`
`
`
` patients with untreated anatomically narrow angles treated with
`
`
`
`
`
`
` antidepressants. (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).
`
`
`
`
`————————— 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 Inc., 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: Based on animal data, may cause fetal harm (8.1).
`
`
`
`
`
`
`
`
`
`
`
` Nursing Mothers: Discontinue drug or nursing taking into consideration
`
`
`
`
`
`
`
`
`
` importance of drug to mother (8.3).
`
`
`
`
`
`
`
` 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: 12/2017
`
`
`
`
`
`
`
`
`
` 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 risk of suicidal thinking and behavior in children,
` adolescents and young adults taking antidepressants (5.1).
`
`
`
`
`
`
` Monitor for worsening and emergence of suicidal thoughts and
`
`
`
`
`
`
`
`
` behaviors (5.1).
`
`
` PRISTIQ is not approved for use in pediatric patients (8.4).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`———————— INDICATIONS AND USAGE ————————
`
`
`
`
`
` PRISTIQ, is a serotonin and norepinephrine reuptake inhibitor (SNRI)
`
`
`
`
`
`
`
`
` 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 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
`
`
`
`
`
`
`
`
`
`
`
` (2.2).
`
`
`
`
`—————— 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 (4.1).
`
`
`
`
`
`
` 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 ——————
`
`
`
`
`
`
`Reference ID: 4197595
`
`
`
`
` 1
`
`

`

` FULL PRESCRIBING INFORMATION: CONTENTS *
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 General Instruction for Use
`
`
`
`
`
`
`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 Patients To or From a Monoamine Oxidase Inhibitor
`
`
`
`
`
`
`
`
`
`
`(MAOI) Intended to Treat Psychiatric Disorders
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Suicidal Thoughts and Behaviors in Children, Adolescents and Young
`
`
`
`
`
`
`
`Adults
`
`
`5.2 Serotonin Syndrome
`
`
`
`
`5.3 Elevated Blood Pressure
`
`
`
`
`
`5.4 Abnormal 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
`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Studies Experience
`
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
`7.1 Monoamine Oxidase Inhibitors (MAOI)
`
`
`
`
`
`
` * Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`7.2 Serotonergic Drugs
`
`
`
`
`7.3 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and
`
`
`
`
`
`
`
`
`Warfarin)
`
`
`7.4 Potential for Other Drugs to Affect Desvenlafaxine
`
`
`
`
`
`
`
`
`7.5 Potential for Desvenlafaxine to Affect Other Drugs
`
`
`
`
`
`
`
`
`
`7.6 Other Drugs Containing Desvenlafaxine or Venlafaxine
`
`
`
`
`
`
`
`7.7 Ethanol
`
`
`
`7.8 Drug-Laboratory Test Interactions
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`8.1 Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`
`8.4 Pediatric Use
`
`
`
`
`8.5 Geriatric Use
`
`
`
`
`8.6 Other Patient Factors
`
`
`
`
`
` 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
`
`
`
`
`
`Reference ID: 4197595
`
`
`
`
` 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)].
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
` PRISTIQ, a 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 short-term
` (8-week, placebo-controlled studies) and two maintenance studies in adult outpatients who met
`
`
`
`DSM-IV criteria for major depressive disorder.
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
` 2.1 GENERAL INSTRUCTION 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
`
`
`Reference ID: 4197595
`
`
`3
`
`
`
`

`

`possible to minimize discontinuation symptoms [see Dosage and Administration (2.4) and
`
` Warnings and Precautions (5.9)].
`
`
`
` 2.2 Special Populations
`
`
`
` Patients with renal impairment
`
` The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine
`
`
`
`
`
`
`
`
`
`
` clearance [CrCl] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum
` recommended dose in patients with severe renal impairment (24-hr CrCl less than 30 mL/min,
`
`
`
`
`
` C-G) or end-stage renal disease (ESRD) 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)].
`
`
`
` Patients with hepatic impairment
`
` The recommended dose in patients with moderate to severe hepatic impairment is 50 mg per
`
`
`
`
`
` day. Dose escalation above 100 mg per day is not recommended [see Clinical Pharmacology
`
`
` (12.3)].
`
`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. 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.
`
`
`
`
`
`
`
`2.4 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. The 25 mg dose is available for discontinuing therapy.
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`Reference ID: 4197595
`
`
`4
`
`
`
`

`

` 2.6 Switching Patients 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)].
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS PRISTIQ® (desvenlafaxine) Extended-Release
`
`
`
`
`
` Tablets are available as 25 mg, 50 mg and 100 mg tablets.
`
`
`
`
` 25 mg, tan, square pyramid tablet debossed with “W” over “25” on the flat side
`
` 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
`
`
`
` 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)].
`
`
`Reference ID: 4197595
`
`
`5
`
`
`
`

`

`
` 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 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults
`
`
`
`
`
` 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 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.
`
`
`
`
` Age Range
`
`
`Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients
`
`Treated
`Increases Compared to Placebo
`
`
`
`Table 1
`
`
`
`Reference ID: 4197595
`
`
`6
`
`
`
`

`

`<18
`
`
` 18 to 24
`
`
` 25 to 64
`≥65
`
`
`
`
`
`
`
`
`14 additional cases
`
`5 additional cases
`Decreases Compared to Placebo
`
` 1 fewer case
`
`6 fewer cases
`
`
`
`
` 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.
`
`
`
`
`
`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) and Warnings and Precautions (5.7)
`
`
`
` 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.
`
`Reference ID: 4197595
`
`
`7
`
`
`
`

`

`
`
` 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, amphetamines, and St. John's Wort), and with drugs that impair
` metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
`
`
`
`
` disorders and also others, such as linezolid and intravenous methylene blue).
`
`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
` 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, amphetamines, tryptophan, and St.
`
`
`
`
`
`
`
` John's Wort is clinically warranted, patients should be made aware of a potential increased risk
` for serotonin syndrome, particularly during treatment initiation and dose increases.
`
`
`
`
` Treatment with PRISTIQ and any concomitant serotonergic agents should be discontinued
`
`
`
`
` immediately if the above events occur and supportive symptomatic treatment should be
`
` initiated.
`
`Reference ID: 4197595
`
`
`8
`
`
`
`

`

`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)].
`
`
`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 Angle Closure Glaucoma
`
`
`
` 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.
`
`
`
`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
`
`
`
`
`
` Discontinuation symptoms have been systematically and prospectively evaluated in patients
`
`treated with PRISTIQ during clinical studies in Major Depressive Disorder. Abrupt
`
` discontinuation or dose reduction has been associated with the appearance of new symptoms
`that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue,
`
` abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more
`
`frequently with longer duration of therapy.
`
`Reference ID: 4197595
`
`
`9
`
`
`
`

`

` During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs
`
`
`
` (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse
` events occurring upon discontinuation of these drugs, particularly when abrupt, including the
`
`following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances
`
` (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy,
` emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are
`
`
`
`
` generally self-limiting, there have been reports of serious discontinuation symptoms.
`
`Patients should be monitored for these symptoms when discontinuing treatment with PRISTIQ.
`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
` [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].
`
`
`
`
`
` 5.8 Seizure
`
`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.
`
`
`
` 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 (12.6)].
`
` 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 progr