DESVENLAFAXINE: 8,922 Adverse Event Reports & Safety Profile

Desvenlafaxine Extended-Release Tablets are an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder. Desvenlafaxine is designated RS -4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C 16 H 25 NO 2 (free base) and C 16 H 25 NO 2

• C 4 H 6 O 4
• H 2 O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below. Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol: aqueous system (at pH 7.0) partition coefficient is 0.21.

Desvenlafaxine

Extended-Release Tablets are formulated as an extended-release tablet for once-a-day oral administration. 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. Inactive ingredients for the 25 mg tablet consist of colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene oxide, talc and film coating, which consists of ferrosoferric oxide, iron oxide red, iron oxide yellow, mono- and di-glycerides, polyethylene glycol polyvinyl alcohol graft copolymer, polyvinyl alcohol, talc and titanium dioxide. Inactive ingredients for the 50 mg tablet consist of colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene oxide, talc and film coating, which consists of iron oxide yellow, iron oxide red, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Inactive ingredients for the 100 mg tablet consist of colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene oxide, talc and film coating, which consists of D&C red #27, FD&C blue #2, FD&C yellow #6, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. chemical structure

AND USAGE Desvenlafaxine, 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 desvenlafaxine has been established in four short-term (8-week, placebo-controlled studies) of outpatients who met DSM-IV criteria for major depressive disorder. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of major depressive disorder (MDD) (1).

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 ).

2.1 General Instructions for Use The recommended dose for desvenlafaxine extended-release tablets is 50 mg once daily, with or without food.

The

50 mg dose is both a starting dose and the therapeutic dose. Desvenlafaxine extended-release tablets 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 ) ] .

2.2 Dosage Recommendations for Patients with Renal Impairment The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance [Cl Cr ] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose in patients with severe renal impairment (Cl Cr 15 to 29 mL/min, C-G) or end-stage renal disease (ESRD, Cl Cr &lt; 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 ) ]</span> .

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 desvenlafaxine extended-release tablets (50 to 400 mg) was established in two maintenance trials <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Patients should be periodically reassessed to determine the need for continued treatment.

2.5 Discontinuing Desvenlafaxine Extended-Release Tablets Adverse reactions may occur upon discontinuation of desvenlafaxine extended-release tablets <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7)]</span>. Gradually reduce the dosage rather than stopping desvenlafaxine extended-release tablets abruptly when discontinuing therapy with desvenlafaxine extended-release tablets. In some patients, discontinuation may need to occur over a period of several months.

2.6 Switching Patients from Other Antidepressants to Desvenlafaxine Extended-Release Tablets Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine extended-release tablets. Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms.

2.7 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 desvenlafaxine extended-release tablets. Conversely, at least 7 days should be allowed after stopping desvenlafaxine extended-release tablets before starting an MAOI intended to treat psychiatric disorders [ see Contraindications ( 4 ) ] .

2.8 Use of Desvenlafaxine Extended-Release Tablets with other MAOIs such as Linezolid or Methylene Blue Do not start desvenlafaxine extended-release tablets 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . In some cases, a patient already receiving desvenlafaxine extended-release tablets 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, desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 desvenlafaxine extended-release tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablets formulation. Angioedema has been reported in patients treated with desvenlafaxine extended-release tablets [see Adverse Reactions ( 6.1 )] . The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine extended-release tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets is contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets 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 )] . Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or any excipients in the desvenlafaxine extended-release tablets formulation ( 4 ).

Serotonin

Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine extended-release tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets. Do not use desvenlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start desvenlafaxine extended-release tablets in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ).

REACTIONS 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) ]
• 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: Desvenlafaxine extended-release tablets may cause symptoms of sexual dysfunction (5.11). 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 Marlex Pharmaceuticals, Inc. at 1-888-582-1953 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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 Desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets; 2,116 were exposed to desvenlafaxine extended-release tablets for 6 months, representing 1,658 patient-years of exposure, and 421 were exposed for one year, representing 416 patient-years of exposure. Adverse reactions reported as reasons for discontinuation of treatment In the pre-marketing pooled 8-week placebo-controlled studies in patient with MDD, 1,834 patients were exposed to desvenlafaxine extended-release tablets (50 to 400 mg). Of the 1,834 patients, 12% discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for desvenlafaxine extended-release tablets (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of desvenlafaxine extended-release tablets the discontinuation rate due to an adverse event was 8.7%. The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than placebo of the desvenlafaxine extended-release tablets treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a long-term study, up to 9 months, the most common was vomiting (2%). Common adverse reactions in placebo-controlled MDD studies The most commonly observed adverse reactions in desvenlafaxine extended-release treated MDD patients in pre-marketing pooled 8-week, placebo-controlled, fixed-dose studies (incidence ≥ 5% and at least 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.

Table

2 shows the incidence of common adverse reactions that occurred in ≥ 2% of desvenlafaxine extended-release treated MDD patients and twice the rate of placebo at any dose in the pre-marketing pooled 8-week, placebo-controlled, fixed dose clinical studies.

Table

2: Common Adverse Reactions (≥2% in any Fixed-Dose Group and Twice the Rate of Placebo) in Pre-marketing Pooled MDD 8-Week Placebo-Controlled Studies Percentage of Patients Reporting Reaction Desvenlafaxine Extended-Release Tablets System Organ Class Preferred Term Placebo (n=636) 50 mg (n=317) 100 mg (n=424) 200 mg (n=307) 400 mg (n=317) Cardiac disorders Blood pressure increased 1 1 1 2 2 Gastrointestinal disorders Nausea 10 22 26 36 41 Dry mouth 9 11 17 21 25 Constipation 4 9 9 10 14 Vomiting 3 3 4 6 9 General disorders and administration site conditions Fatigue 4 7 7 10 11 Chills 1 1 <1 3 4 Feeling jittery 1 1 2 3 3 Metabolism and nutrition disorders Decreased appetite 2 5 8 10 10 Nervous system disorders Dizziness 5 13 10 15 16 Somnolence 4 4 9 12 12 Tremor 2 2 3 9 9 Disturbance in attention <1 <1 1 2 1 Psychiatric disorders Insomnia 6 9 12 14 15 Anxiety 2 3 5 4 4 Nervousness 1 <1 1 2 2 Abnormal dreams 1 2 3 2 4 Renal and urinary disorders Urinary hesitation 0 <1 1 2 2 Respiratory, thoracic and mediastinal disorders Yawning <1 1 1 4 3 Skin and subcutaneous tissue disorders Hyperhidrosis 4 10 11 18 21 Special Senses Vision blurred 1 3 4 4 4 Mydriasis <1 2 2 6 6 Vertigo 1 2 1 5 3 Tinnitus 1 2 1 1 2 Dysgeusia 1 1 1 1 2 Vascular disorders Hot flush <1 1 1 2 2 Sexual function adverse reactions Table 3 shows the incidence of sexual function adverse reactions that occurred in ≥ 2% of desvenlafaxine extended-release tablets treated MDD patients in any fixed-dose group (pre-marketing pooled 8-week, placebo-controlled, fixed-dose, clinical studies). [See Warnings and Precautions (5.11)].

Table

3: Sexual Function Adverse Reactions (≥2% in Men or Women in any Desvenlafaxine Extended-Release Tablets Group) During the On-Therapy Period Desvenlafaxine Extended-Release Tablets Placebo (n=239) 50 mg (n=108) 100 mg (n=157) 200 mg (n=131) 400 mg (n=154) Men only Anorgasmia 0 0 3 5 8 Libido decreased 1 4 5 6 3 Orgasm abnormal 0 0 1 2 3 Ejaculation delayed <1 1 5 7 6 Erectile dysfunction 1 3 6 8 11 Ejaculation disorder 0 0 1 2 5 Ejaculation failure 0 1 0 2 2 Sexual dysfunction 0 1 0 0 2 Desvenlafaxine Extended-Release Tablets Placebo (n=397) 50 mg (n=209) 100 mg (n=267) 200 mg (n=176) 400 mg (n=163) Women only Anorgasmia 0 1 1 0 3 Other adverse reactions observed in premarketing and postmarketing clinical studies Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with desvenlafaxine extended-release tablets were: Cardiac disorders – Tachycardia. General disorders and administration site conditions – Asthenia. Investigations – Weight increased, liver function test abnormal, blood prolactin increased. Musculoskeletal and connective tissue disorders – Musculoskeletal stiffness. Nervous system disorders – Syncope, convulsion, dystonia Psychiatric disorders – Depersonalization, bruxism. Renal and urinary disorders – Urinary retention Skin and subcutaneous tissue disorders – Rash, alopecia, photosensitivity reaction, angioedema In clinical studies, there were uncommon reports of ischemic cardiac adverse reactions, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine extended-release tablets treatment as compared to placebo. Laboratory, ECG and vital sign changes observed in MDD clinical studies The following changes were observed in pre-marketing placebo-controlled, short-term MDD studies with desvenlafaxine extended-release tablets.

Lipids

Elevations in fasting serum total cholesterol, LDL (low density lipoproteins) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant. The percentage of patients who exceeded a predetermined threshold value is shown in Table 4.

Table

4: Incidence (%) of Patients With Lipid Abnormalities of Potential Clinical Significance* Desvenlafaxine Extended-Release Tablets Placebo 50 mg 100 mg 200 mg 400 mg Total Cholesterol *(Increase of ≥ 50 mg/dl and an absolute value of ≥ 261 mg/dl) 2 3 4 4 10 LDL Cholesterol *(Increase ≥ 50 mg/dl and an absolute value of ≥ 190 mg/dl) 0 1 0 1 2 Triglycerides, fasting *(Fasting: ≥ 327 mg/dl) 3 2 1 4 6 Proteinuria Proteinuria, greater than or equal to trace, was observed in the pre-marketing fixed-dose controlled studies (see Table 5). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.

Table

5: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical Studies Desvenlafaxine Extended-Release Tablets Placebo 50 mg 100 mg 200 mg 400 mg Proteinuria 4 6 8 5 7 Vital sign changes Table 6 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine extended-release tablets in patients with MDD (doses 50 to 400 mg).

Table

6: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled Studies Desvenlafaxine Extended-Release Tablets Placebo 50 mg 100 mg 200 mg 400 mg Blood pressure Supine systolic bp (mm Hg) -1.4 1.2 2.0 2.5

2.1 Supine diastolic bp (mm Hg) -0.6 0.7 0.8 1.8

2.3 Pulse rate Supine pulse (bpm) -0.3 1.3 1.3 0.9

4.1 Weight (kg) 0.0 -0.4 -0.6 -0.9 -1.1 Treatment with desvenlafaxine extended-release tablets at all doses from 50 mg per day to 400 mg per 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 7). Analyses of patients in desvenlafaxine extended-release tablets pre-marketing short-term controlled studies who met criteria for substantial 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 per day.

Table

7: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood Pressure Treatment Group Proportion of Patients with Sustained Hypertension Placebo 0.5% Desvenlafaxine ER Tablets 50 mg per day 1.3% Desvenlafaxine ER Tablets 100 mg per day 0.7% Desvenlafaxine ER Tablets 200 mg per day 1.1% Desvenlafaxine ER Tablets 400 mg per day 2.3% Orthostatic hypotension In the pre-marketing short-term, placebo-controlled clinical studies with doses of 50 to 400 mg, systolic orthostatic hypotension (decrease ≥ 30 mm Hg from supine to standing position) occurred more frequently in patients ≥ 65 years of age receiving desvenlafaxine extended-release tablets (8%, 7/87) versus placebo (2.5%, 1/40), compared to patients < 65 years of age receiving desvenlafaxine extended-release tablets (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).

6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of desvenlafaxine extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Skin and subcutaneous tissue disorders – Stevens-Johnson syndrome Gastrointestinal disorders - Pancreatitis acute Cardiovascular system – Takotsubo cardiomyopathy Respiratory, thoracic and mediastinal disorders – Anosmia, hyposmia

AND PRECAUTIONS Serotonin Syndrome: Increased risk when coadministered with other serotonergic agents, but also when taken alone. If it occurs, discontinue desvenlafaxine extended-release tablets and serotonergic agents 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 desvenlafaxine extended-release tablets, 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: Desvenlafaxine extended-release tablets may cause symptoms of sexual dysfunction ( 5.11 ).

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients 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.

Table

1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 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 ), 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 desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets are not approved for use in treating bipolar depression.

5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including desvenlafaxine extended-release tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.1 )]</span> . 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 desvenlafaxine extended-release tablets with MAOIs is contraindicated. In addition, do not initiate desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets, discontinue desvenlafaxine extended-release tablets before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.1 ) ]</span> . Monitor all patients taking desvenlafaxine extended-release tablets for the emergence of serotonin syndrome. Discontinue treatment with desvenlafaxine extended-release tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Pre-existing hypertension should be controlled before initiating treatment with desvenlafaxine extended-release tablets. 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 desvenlafaxine extended-release tablets. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving desvenlafaxine extended-release tablets, either dose reduction or discontinuation should be considered <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including desvenlafaxine extended-release tablets, 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. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of desvenlafaxine extended-release tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing desvenlafaxine extended-release tablets.

5.5 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets, 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 desvenlafaxine extended-release tablets. 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, desvenlafaxine extended-release tablets 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. There have been postmarketing reports of serious discontinuation symptoms with desvenlafaxine extended-release tablets, which can be protracted and severe. Completed suicide, suicidal thoughts, and severe aggression (including hostility, rage, and homicidal ideation) have been observed in patients during reduction in desvenlafaxine extended-release tablets dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of desvenlafaxine extended-release tablets. Patients should be monitored when discontinuing treatment with desvenlafaxine extended-release tablets. A gradual reduction in the dose, rather than abrupt cessation, is recommended. 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 healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.8 Seizure Cases of seizure have been reported in pre-marketing clinical studies with desvenlafaxine extended-release tablets. Desvenlafaxine extended-release tablets have not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from pre-marketing clinical studies. Desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 ) and Clinical Pharmacology ( 12.3 )]</span> . Discontinuation of desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with desvenlafaxine extended-release tablets who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of desvenlafaxine extended-release tablets should be considered.

5.11 Sexual Dysfunction Use of SNRIs, including desvenlafaxine extended-release tablets, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 desvenlafaxine extended-release tablets 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.

INTERACTIONS

7.1 Monoamine Oxidase Inhibitors (MAOI) Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine. Do not use desvenlafaxine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start desvenlafaxine in a patient who is being treated with linezolid or intravenous methylene blue <span class="opacity-50 text-xs">[see Dosage and Administration (2.6 ), Contraindications (4) and Warnings and Precautions (5.2)]</span>.

7.2 Serotonergic Drugs Based on the mechanism of action of desvenlafaxine and the potential for serotonin syndrome, caution is advised when desvenlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems <span class="opacity-50 text-xs">[see Dosage and Administration (2.6), Contraindications (4) and Warnings and Precautions (5.2)]</span>.

7.3 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when desvenlafaxine is initiated or discontinued <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4)]</span>.

7.4 Potential for Desvenlafaxine to Affect Other Drugs Based on in vitro data, no dose adjustment is required for desvenlafaxine when used concomitantly with inhibitors of CYP3A4 and CYP1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, 2E1, and the P-glycoprotein transporter. Clinical studies have demonstrated no clinically significant pharmacokinetic interaction between desvenlafaxine and strong CYP 3A4 inhibitors (Figure 1).

Figure

1

7.5 Potential for Desvenlafaxine to Affect Other Drugs Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily (Figure 2). Substrates primarily metabolized by CYP2D6 (e.g., desipramine , atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) should be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. Reduce the dose of these substrates by up to one-half if co-administered with 400 mg of desvenlafaxine. No additional dose adjustment is required for concomitant use of substrates of CYP3A4, 1A2, 2A6, 2C8, 2C9, and 2C19 isozymes, and P-glycoprotein transporter. Clinical studies have demonstrated no clinically significant pharmacokinetic interaction between desvenlafaxine and CYP3A4 substrates (Figure 2). Clinical studies have shown that desvenlafaxine (100 mg daily) does not have a clinically relevant effect on tamoxifen and aripiprazole, compounds that are metabolized by a combination of both CYP2D6 and CYP3A4 enzymes (Figure 2). In vitro studies showed minimal inhibitory effect of desvenlafaxine on the CYP2D6 isoenzyme. In vitro , desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. In vitro , desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19, isozymes, and P-glycoprotein transporter and would not be expected to affect the pharmacokinetics of drugs that are substrates of these CYP isozymes and transporter.

Figure

2

7.6 Other Drugs Containing Desvenlafaxine or Venlafaxine Avoid use of desvenlafaxine with other desvenlafaxine-containing products or venlafaxine products. The concomitant use of desvenlafaxine with other desvenlafaxine-containing products or venlafaxine will increase desvenlafaxine blood levels and increase dose-related adverse reactions <span class="opacity-50 text-xs">[see Adverse Reactions (6)]</span>.

7.7 Ethanol A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine.

7.8 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.