Desvenlafaxine

Desvenlafaxine is indicated for the treatment of adults with major depressive disorder (MDD) [see Clinical Studies (14)] . Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of adults with major depressive disorder (MDD) (1).

Desvenlafaxine extended-release tablets are available as 50 and 100 mg tablets. 50 mg, light pink colored, diamond shaped, biconvex tablets, debossed with ‘L189’ on one side and plain on other side. 100 mg, dark brown to red colored, diamond shaped, biconvex tablets, debossed with ‘L190’ on one side and plain on other side. Desvenlafaxine extended-release tablets are available as 50 and 100 mg tablets (3)

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 [see Adverse Reactions (6.1)] . The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine is contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine 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 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 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 (4).

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue desvenlafaxine 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, 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 may cause symptoms of sexual dysfunction (5.11).

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients 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. 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 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 is 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, 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. […]

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)] 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 Alembic Pharmaceuticals Limited at 1-800-406-7984 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 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; 2,116 were exposed to desvenlafaxine 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 patients with MDD, 1,834 patients were exposed to desvenlafaxine (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 (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of desvenlafaxine the discontinuation rate due to an adverse reaction 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 treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-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 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 treated MDD patients and twice the rate of placebo at any dose in the 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 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 treated MDD patients in any fixed-dose group (pre-marketingpooled 8-week, placebo-controlled, fixed -dose, clinical studies). Table 3: Sexual Function Adverse Reactions (≥2% in Men or Women in any Desvenlafaxine Group) During the On-Therapy Period Desvenlafaxine 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 Placebo (n=397) Desvenlafaxine 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 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 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. 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 Placebo 50 mg 100 mg 200 mg 400 mg Total Cholesterol 2 3 4 4 10 *(Increase of ≥ 50 mg/dl and an absolute value of ≥ 261 mg/dl) LDL Cholesterol 0 1 0 1 2 *(Increase ≥ 50 mg/dl and an absolute value of ≥ 190 mg/dl) Triglycerides, fasting 3 2 1 4 6 *(Fasting: ≥ 327 mg/dl) Proteinuria Proteinuria, greater than or equal to trace, was observed in the pre-marketingfixed-dose controlled studies (see Table 5). This proteinuria was not associated with increases in BUN or creatinine and was generally transient. […]

7.1 Drugs Having Clinically Important Interactions with Desvenlafaxine Table 8: Clinically Important Drug Interactions with Desvenlafaxine Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SSRIs and SNRIs including desvenlafaxine with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of desvenlafaxine is contraindicated:

• With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with desvenlafaxine.
• Within 14 days of stopping an MAOI intended to treat psychiatric disorders.
• In a patient who is being treated with linezolid or intravenous methylene blue. [see Dosage and Administration (2.7), Contraindications (4) and Warnings and Precautions (5.2)]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of desvenlafaxine with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when desvenlafaxine is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of desvenlafaxine and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)]. Examples Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John’s Wort Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of desvenlafaxine with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of desvenlafaxine on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when desvenlafaxine is initiated or discontinued [see Warnings and Precautions (5.4)] . Examples NSAIDs, aspirin, and warfarin Drugs that are Primarily Metabolized by CYP2D6 Clinical Impact Concomitant use of desvenlafaxine increases C max and AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug [see Clinical Pharmacology (12.3)] . Intervention Original dose should be taken when co-administered with desvenlafaxine 100 mg or lower. Reduce the dose of these drugs by up to one-half if co-administered with 400 mg of desvenlafaxine. Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine

7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine [see Clinical Pharmacology (12.3)].

7.3 Alcohol 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.

7.4 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.

Pregnancy: Third trimester use may result in neonatal discontinuation syndrome (8.1). Geriatric Use: There is an increased incidence of orthostatic hypotension in desvenlafaxine treated patients ≥ 65 years (6.1 and 8.5).

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185. Risk summary Based on data from 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 [see Warnings and Precautions (5.4) and Clinical Considerations]. There are no published studies on desvenlafaxine in pregnant women; however published epidemiologic studies of pregnant women exposed to venlafaxine, the parent compound, have not reported a clear association with adverse developmental outcomes (see Data) . There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including desvenlafaxine, during pregnancy ( see Clinical Considerations). In reproductive developmental studies in rats and rabbits treated with desvenlafaxine succinate, there was no evidence of teratogenicity at a plasma exposure (AUC) that is up to 19-times (rats) and 0.5-times (rabbits) the exposure at an adult human dose of 100 mg per day. However, fetotoxicity and pup deaths were observed in rats at 4.5-times the AUC exposure observed with an adult human dose of 100 mg per day. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Maternal adverse reactions Exposure to desvenlafaxine in mid to late pregnancy may increase the risk for preeclampsia, and exposure to desvenlafaxine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.4)]. Fetal/Neonatal adverse reactions Exposure to SNRIs or SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Monitor neonates who were exposed to desvenlafaxine in the third trimester of pregnancy for drug discontinuation syndrome (see Data). Data Human Data Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage. Methodological limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies cannot establish or exclude any drug-associated risk during pregnancy. Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted (adj) RR 1.57, 95% CI 1.29 to 1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg/day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10 to 20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg/day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders. Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24, 95% CI 1.69 to 2.97). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64 to 1.76). The results of this study may be confounded by the effects of depression. Neonates exposed to SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)] . Animal Data When desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day. When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was a decrease in pup weights and an increase in pup deaths during the first four days of lactation at the highest dose of 300 mg/kg/day. The cause of these deaths is not known. The AUC exposure at the no-effect dose for rat pup mortality was 4.5-times the AUC exposure at an adult human dose of 100 mg per day. Post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine succinate at exposures 19 times the AUC exposure at an adult human dose of 100 mg per day.

8.2 Lactation Risk Summary Available limited data from published literature show low levels of desvenlafaxine in human milk, and have not shown adverse reactions in breastfed infants ( see Data) . There are no data on the effects of desvenlafaxine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for desvenlafaxine and any potential adverse effects on the breastfed child from desvenlafaxine or from the underlying maternal condition. […]

The exact mechanism of the antidepressant action of desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).