AHFS Class:

• Selective Serotonin- and Norepinephrine-reuptake Inhibitors 28:16.04.16

Generic Name(s):

• Desvenlafaxine

• Desvenlafaxine Succinate

Desvenlafaxine and its succinate salt (desvenlafaxine succinate) are selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs); desvenlafaxine is the principal active metabolite of venlafaxine.1,3,4,5,19,34,35,38,53

Major Depressive Disorder

Desvenlafaxine is used in the treatment of major depressive disorder in adults.1,3,5,53

Clinical Experience

The antidepressant efficacy of desvenlafaxine has been established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies of 8 weeks' duration in adult outpatients who met DSM-IV criteria for major depressive disorder.1,3,5 In all of these studies, patients receiving desvenlafaxine (50-400 mg daily as extended-release tablets) demonstrated greater improvement in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score than did patients receiving placebo.1,3,5 Patients receiving desvenlafaxine also demonstrated greater overall improvement as measured by the Clinical Global Impressions Scale-Improvement (CGI-I) compared with placebo recipients in 3 out of 4 of these studies.1,3,5 In the 2 studies that directly compared 50 mg and 100 mg of desvenlafaxine given once daily, there was no evidence of a greater therapeutic effect at the higher 100-mg dosage.1 In addition, adverse effects and drug discontinuances were reported more frequently at higher dosages of the drug in these studies.1,3,5 No age- or gender-related differences in efficacy were noted in these studies; data were insufficient to determine whether there were race-related differences in efficacy.1

Longer-term studies with desvenlafaxine have also been conducted.1,42,49 In one trial, adults with major depressive disorder who responded to 8 weeks of open-label desvenlafaxine (50 mg per day) and subsequently remained stable on treatment for 12 weeks were randomized in a double-blind manner to continue desvenlafaxine or switch to placebo for up to 26 weeks.1,42 Patients were monitored for relapse of depression (defined as HAMD-17 score ≥16 at any visit, discontinuation of treatment due to lack of efficacy, hospitalization for depression, suicide attempt, or suicide).1,42 Compared to placebo, patients who continued on desvenlafaxine had a longer time to relapse.1,42 At 26 weeks, 14.3 or 30.2% of patients had a relapse of depression with desvenlafaxine or placebo, respectively.1,42

In another longer-term trial, adults with major depressive disorder responding to 12 weeks of treatment with desvenlafaxine were randomized in a double-blind manner to continue the same dose of desvenlafaxine (200 or 400 mg per day) or switch to placebo for up to 26 weeks.1 Relapse was defined as a HAMD-17 score ≥16 at any visit, CGI-I score ≥6 at any visit, or discontinuation of study drug due to unsatisfactory response.1 At 26 weeks, the rate of relapse was 29 or 49% with desvenlafaxine or placebo, respectively.1

A postmarketing randomized double-blind trial evaluated the efficacy of desvenlafaxine 25 or 50 mg versus placebo in 699 adult patients with major depressive disorder.1,49 Based on the primary efficacy measure (change from baseline in HAMD-17 total score), desvenlafaxine 50 mg was superior to placebo, but desvenlafaxine 25 mg was not.1,49 Change in HAMD-17 score from baseline was -10.02, -8.98, or -8.52 for desvenlafaxine 50 mg, desvenlafaxine 25 mg, or placebo, respectively.49

Clinical Perspective

Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.50,51,54,55 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.50,51,54,55 In general, these drugs have shown similar effectiveness; therefore, treatment is guided by specific patient and drug-related factors.50,54,55

A legacy practice guideline from the American Psychiatric Association (APA) published in 2010 states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of medications, including selective serotonin reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and other antidepressants (e.g., bupropion, mirtazapine, trazodone).50 Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; response to prior therapies; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, cytochrome P-450 [CYP] interactions, other drug interactions); and cost.50

The Department of Veterans Affairs and Department of Defense developed more current guidelines for the management of major depressive disorder.51 These guidelines state that treatment of uncomplicated major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.51 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, a selective serotonin reuptake inhibitor (SSRI), a SNRI, trazodone, vilazodone, or vortioxetine is suggested.51 No evidence is available to suggest superiority of one agent over another.51 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.51 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.51

Vasomotor Symptoms

Like some other SNRIs and SSRIs, desvenlafaxine succinate has been studied for the management of vasomotor symptoms† in postmenopausal women.10,11,25,26,29,30,31,32,33,34,37,38

Guidelines from the North American Menopause Society recommend several treatments for vasomotor symptoms associated with menopause, including cognitive-behavioral therapy, SNRIs (including desvenlafaxine), SSRIs, fezolinetant, and gabapentin.52

General

Pretreatment Screening

• Perform a detailed psychiatric history (including family history of suicide, bipolar disorder, and depression) to assess risk of bipolar disorder prior to starting desvenlafaxine.1,53
• Control preexisting hypertension before initiating desvenlafaxine therapy; use caution in patients with preexisting hypertension, cardiovascular, or cerebrovascular conditions that may be compromised by blood pressure increases.1,53
• Inquire about sexual function prior to initiation of desvenlafaxine.1,53

Patient Monitoring

• Monitor for worsening depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.1,53
• Monitor blood pressure regularly.1,53
• Monitor for development of serotonin syndrome.1,53
• In patients receiving concomitant warfarin, monitor coagulation indices and look for signs of bleeding during initiation, titration, or discontinuance of desvenlafaxine.1,53
• When discontinuing desvenlafaxine, monitor for discontinuance symptoms (e.g., nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances, tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures).1
• Inquire about changes in sexual function during treatment.1,53

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for desvenlafaxine succinate (Pristiq^®) on the prescription order form.41

Other General Considerations

• Acute episodes of major depressive disorder typically require pharmacologic treatment for several months or longer; reassess patients periodically to determine need for continued treatment.1,53
• When discontinuing therapy, reduce dosage gradually and monitor for possible withdrawal symptoms; avoid abrupt discontinuance whenever possible.1,53 Some patients require discontinuation over a period of several months.1 If intolerable symptoms occur following dosage reduction or upon discontinuance of therapy, consider resuming therapy at the previously prescribed dosage and decreasing the dosage at a more gradual rate.1
• If switching to desvenlafaxine from a monoamine oxidase inhibitor (MAOI) intended to treat psychiatric disorders, allow 14 days to elapse between discontinuation of the MAOI and initiation of desvenlafaxine.1,53 Conversely, if switching from desvenlafaxine to an MAOI, allow 7 days to elapse between discontinuation of desvenlafaxine and initiation of the MAOI.1,53
• When switching from another antidepressant to desvenlafaxine, it may be necessary to taper the dosage of the previous antidepressant to minimize discontinuance symptoms.1,53
• Do not initiate desvenlafaxine in patients receiving linezolid or IV methylene blue; if urgent treatment with linezolid or IV methylene blue is required in a patient receiving desvenlafaxine, stop desvenlafaxine and monitor for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or IV methylene blue (whichever comes first).1,53 Resume desvenlafaxine 24 hours after the last dose of linezolid or IV methylene blue.1,53

Administration

Desvenlafaxine and desvenlafaxine succinate are administered orally and are available as extended-release tablets.1,53

Administer desvenlafaxine and desvenlafaxine succinate with or without food at approximately the same time each day.1,53 Extended-release tablets should be swallowed whole with fluid and should not be divided, crushed, chewed, or dissolved.1,53

Store at 20-25ºC (excursions permitted between 15-30ºC).1,53

Dosage

Dosage of desvenlafaxine succinate is expressed in terms of desvenlafaxine.1

Major Depressive Disorder

For the management of major depressive disorder in adults, the recommended dosage of desvenlafaxine is 50 mg once daily.1,53 Although efficacy has been established at dosages of 50-400 mg once daily in clinical studies, no additional benefit was observed with dosages greater than 50 mg once daily, and adverse effects and discontinuances were more frequent at higher dosages.1,53 The 25-mg per day dose is intended for gradual reduction in dose when discontinuing treatment.1

Vasomotor Symptoms

For the management of vasomotor symptoms in postmenopausal women†, guidelines suggest an initial desvenlafaxine dosage of 25-50 mg daily; the dosage may be titrated up by that amount each day.52 The effective dosage range is usually 100-150 mg daily.52

Special Populations

Hepatic Impairment

The manufacturers make no specific dosage recommendations in mild hepatic impairment.1,53 In patients with moderate to severe hepatic impairment (Child-Pugh score 7-15), the recommended desvenlafaxine dosage is 50 mg given once daily.1,53 Dosages exceeding 100 mg daily are not recommended.1,53

Renal Impairment

The manufacturers make no specific dosage recommendations in mild renal impairment (creatinine clearance >50 mL/minute based on Cockcroft-Gault).1,53 In patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute), the maximum recommended desvenlafaxine dosage is 50 mg given once daily.1,53 The maximum recommended dosage in patients with severe renal impairment (creatinine clearance 15-29 mL/minute) or end-stage renal disease (creatinine clearance <15 mL/minute) is 25 mg once daily or 50 mg given every other day.1,53 Supplemental doses should not be administered to patients after dialysis.1,53

Geriatric Patients

Although there are no specific dosage recommendations for desvenlafaxine in geriatric patients, the possibility of reduced renal clearance of the drug should be considered when determining dosage.1,53

Contraindications

• Known hypersensitivity to desvenlafaxine, venlafaxine hydrochloride, or any ingredient in the formulation.1,53
• Concurrent or recent (i.e., within 14 days) therapy with a monoamine oxidase inhibitor (MAOI) intended to treat psychiatric disorders.1,53 Use of an MAOI intended to treat psychiatric disorders within 7 days of desvenlafaxine discontinuance.1,53
• Initiation of desvenlafaxine therapy in patients receiving MAOIs such as linezolid or IV methylene blue.1,53

Warnings/Precautions

Warnings

Suicidal Thoughts and Behaviors

A boxed warning regarding an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults is included in the prescribing information for desvenlafaxine.1,53 Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants.1,53 This risk may persist until clinically important remission occurs.1,53 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1,53 However, there has been a long-standing concern 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.1,53 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1,53 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults ≥65 years of age.1,53 All patients being treated with antidepressants for any indication should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1,53 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1,53 Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania 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.1,53 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.1,53 It is also recommended that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1,53 Because bipolar disorder may initially present as a major depressive episode, screen patients with depressive symptoms to determine the risk of bipolar disorder prior to initiating desvenlafaxine.1,53 Screening should include a detailed psychiatric history (including family history of suicide, bipolar disorder, and depression).1,53 Although not established in controlled clinical studies, it is thought that treatment of bipolar disorder with an antidepressant alone may precipitate the development of a mixed/manic episode in patients at risk for bipolar disorder.1,53 Desvenlafaxine is not indicated for use in the treatment of bipolar disorder.1,53

Other Warnings and Precautions

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported with SSRIs and serotonin- and norepinephrine-reuptake inhibitors (SNRIs) alone, including desvenlafaxine, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, St. John's Wort [ Hypericum perforatum ]) and drugs that impair the metabolism of serotonin (e.g., MAOIs).1,53 Signs and symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, 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 GI symptoms (e.g., nausea, vomiting, diarrhea).1,53 Patients receiving desvenlafaxine should be monitored for the development of serotonin syndrome.1,53 If use of desvenlafaxine with other serotonergic drugs is warranted, inform patients of the risk for serotonin syndrome, and monitor for symptoms.1,53

Concurrent or recent (i.e., within 14 days) therapy with MAOIs used for treatment of psychiatric disorders is contraindicated.1,53 Desvenlafaxine should not be initiated in patients receiving MAOIs such linezolid or IV methylene blue.1,53 If an MAOI such as linezolid or IV methylene blue is necessary in a patient receiving desvenlafaxine, discontinue desvenlafaxine before initiating the MAOI and monitor for serotonin syndrome for 7 days or until 24 hours after the last dose of the MAOI (whichever comes first).1,53

If serotonin syndrome occurs, immediately discontinue treatment with desvenlafaxine and any concurrently administered serotonergic agents, and initiate supportive symptomatic treatment.1,53

Elevated Blood Pressure

Because of observed increases in blood pressure in clinical studies of desvenlafaxine, regular monitoring of blood pressure is recommended in patients receiving the drug.1,53

Sustained blood pressure increases could have adverse consequences in patients receiving the drug.1,53 Therefore, the manufacturers recommend that preexisting hypertension be controlled before initiating desvenlafaxine therapy.1,53 Desvenlafaxine should be used cautiously in patients with preexisting hypertension, cardiovascular, or cerebrovascular conditions that may be compromised by increases in blood pressure.1,53 Dosage reduction or drug discontinuance should be considered in patients who experience a sustained increase in blood pressure during therapy.1,53

Increased Risk of Bleeding

SSRIs and SNRIs, including desvenlafaxine, may increase the risk of bleeding events.1,53 Concurrent administration of aspirin, nonsteroidal anti-inflammatory agents, warfarin, and other anticoagulants may add to this risk.1,53 Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding.1,53 Observational data indicate that exposure to SNRIs, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage, particularly during the month before delivery.1,53

The manufacturers recommend that patients be advised of the risk of bleeding associated with the concomitant use of desvenlafaxine and antiplatelet agents or anticoagulants.1,53 For patients receiving warfarin therapy, careful coagulation monitoring is recommended during initiation, titration, and discontinuation of desvenlafaxine.1,53

Angle Closure Glaucoma

Many antidepressant drugs, including desvenlafaxine, may cause pupillary dilation, which can trigger an angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.1,53 Avoid use of desvenlafaxine and other antidepressants in patients with untreated anatomically narrow angles.1,53

Activation of Mania/Hypomania

Mania was reported in approximately 0.02% of desvenlafaxine-treated patients during clinical studies for major depressive disorder.1,53 Activation of mania/hypomania has also been reported in some patients treated with other antidepressants.1,53 Use with caution in patients with a personal or family history of mania or hypomania.1,53

Discontinuation Syndrome

Abrupt discontinuance of serotonergic antidepressants has been associated with the appearance of adverse effects, including nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.1,53

There have also been postmarketing reports of serious discontinuation symptoms with desvenlafaxine, some protracted and severe.1 Completed suicide, suicidal thoughts, and severe aggression have been reported during desvenlafaxine dosage reduction and discontinuation.1 Visual changes (i.e., blurred vision, trouble focusing) and increased blood pressure have also been reported after stopping or reducing the dosage of desvenlafaxine.1 Therefore, patients should be monitored for possible withdrawal symptoms when discontinuing desvenlafaxine therapy.1 A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.1 If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage, then resume more gradual dosage reductions.1 Some patients may require discontinuation of desvenlafaxine over a period of several months.1

Seizures

Seizures have been reported in premarketing clinical studies of desvenlafaxine.1,53 Desvenlafaxine has not been systematically evaluated in patients with seizure disorders; such patients were excluded from premarketing clinical studies.1,53 The manufacturers state that the drug should be used with caution in patients with a seizure disorder.1,53

Hyponatremia

Treatment with SSRIs and SNRIs, including desvenlafaxine, may result in hyponatremia.1,53 In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1,53 Cases with serum sodium concentrations lower than 110 mmol/L have been reported.1,53 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia.1,53 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death.1,53 Initiate appropriate medical intervention and consider drug discontinuance in patients with symptomatic hyponatremia.1,53

Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of desvenlafaxine) have been reported rarely.1,53 The possibility of such adverse effects should be considered in patients treated with desvenlafaxine who present with progressive dyspnea, cough, or chest discomfort.1,53 Such patients should be evaluated promptly and discontinuance of desvenlafaxine should be considered.1,53

Sexual Dysfunction

Sexual dysfunction can occur with the use of SNRIs, including desvenlafaxine; this can include ejaculatory delay or failure, decreased libido, or erectile dysfunction in males, and decreased libido or delayed/absent orgasm in females.1,53

Providers should inquire about sexual function prior to initiation and during treatment with desvenlafaxine, since sexual function may not be spontaneously reported.1,53 Obtaining a detailed history, including time of symptom onset, is important when evaluating changes in sexual function, since sexual symptoms can have other causes (including the underlying psychiatric disorder).1,53 Potential management strategies should be discussed to support patients in making informed treatment decisions.1,53

Specific Populations

Pregnancy

The National Pregnancy Registry for Antidepressants monitors pregnancy outcomes in women exposed to desvenlafaxine during pregnancy.1,53 Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185.1,53

No published studies are available on desvenlafaxine use in pregnancy; however, available epidemiologic data with venlafaxine (parent compound) in pregnant women have not found a clear association between venlafaxine and adverse developmental outcomes.1,53

There are risks associated with both untreated depression and exposure to SNRIs or SSRIs during pregnancy.1,53 A longitudinal study of women with a history of major depression who discontinued antidepressants during pregnancy found that these women were more likely to experience a relapse of major depression compared to women who continued treatment.1,53

The risk of preeclampsia may be increased with desvenlafaxine exposure in mid to late pregnancy.1,53 Observational data indicate that exposure to SNRIs, particularly during the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.1,53

Some neonates exposed to SNRIs or SSRIs late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, and tube feeding.1,53 Such complications may arise immediately upon delivery.1,53 Clinical findings reported to date in neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.1,53 These clinical features appear to be consistent with either a direct toxic effect of the SNRI or SSRI or, possibly, a drug withdrawal syndrome.1,53 It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome.1,53 Neonates exposed to desvenlafaxine during the third trimester of pregnancy should be monitored for discontinuation syndrome.1,53

Lactation

Desvenlafaxine is excreted into human milk at low levels, and adverse reactions have not been detected in breast-fed infants exposed to desvenlafaxine through breast milk.1,53 It is not known if desvenlafaxine affects milk production.1,53 Consider the developmental and health benefits of breastfeeding, the mother's clinical need for the drug, and the potential for adverse effects on the breast-fed infant from exposure to desvenlafaxine or the underlying maternal condition.1,53

Pediatric Use

Safety and effectiveness of desvenlafaxine for major depressive disorder in pediatric patients younger than 18 years of age have not been established.1,53 Desvenlafaxine failed to demonstrate efficacy for major depressive disorder in patients 7-17 years of age in 2 randomized studies conducted over an 8-week period.1

A greater risk of suicidal thinking or behavior (suicidality) is associated with antidepressant treatment in children and adolescents with major depressive disorder.1,53 Decreases in body weight were also observed in short-term pediatric clinical trials of desvenlafaxine, with a ≥3.5% weight loss from baseline occurring in 22% and 14% of patients receiving low dose and high dose desvenlafaxine, respectively, compared to 7% of patients receiving placebo.1 Six-month extension studies of desvenlafaxine in pediatric patients 7-17 years of age with major depressive disorder demonstrated mean changes in weight similar to the expected changes in pediatric patients based on age and sex.1

Desvenlafaxine exposure was approximately 30% higher in pediatric patients 7-11 years of age compared to adult patients receiving the same dose.1 Desvenlafaxine exposure was similar in adolescents 12-17 years of age and adult patients.1

Geriatric Use

In clinical studies of desvenlafaxine, 6% of patients were ≥65 years of age.1,53 Although no overall differences in safety or efficacy were observed between geriatric and younger patients in these studies, a higher incidence of systolic orthostatic hypotension was reported in patients ≥65 years of age compared with younger patients who received desvenlafaxine.1,53 Consider possible reduced renal clearance of the drug in geriatric patients when determining dosage.1,53

SSRIs and SNRIs, including desvenlafaxine, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1,53

Hepatic Impairment

In patients with moderate to severe (Child-Pugh score 7-15) hepatic impairment, AUC of desvenlafaxine was increased by approximately 31-35%.1,53 The recommended desvenlafaxine dosage in patients with moderate to severe hepatic impairment is 50 mg daily; dosages exceeding 100 mg daily are not recommended in such patients.1,53

Renal Impairment

In patients with moderate or severe renal impairment (creatinine clearance 15-50 mL/minute based on Cockcroft-Gault) or end-stage renal disease (creatinine clearance <15 mL/minute based on Cockcroft Gault), clearance of desvenlafaxine was decreased, resulting in potentially clinically significant increases in drug exposure.1,53 Dosage adjustment is necessary in such patients.1,53 In pharmacokinetic studies, AUC was increased approximately 42% in mild renal impairment (creatinine clearance 50-80 mL/minute based on Cockcroft-Gault), 56% in moderate renal impairment (creatinine clearance 30-49 mL/minute), 108% in severe renal impairment (creatinine clearance 15-29 mL/minute), and approximately 116% in patients with end-stage renal disease (creatinine clearance <15 mL/minute), compared to the reference population.1,53

Common Adverse Effects

Adverse effects reported in at least 5% of patients with major depressive disorder receiving desvenlafaxine (50 or 100 mg daily) and at an incidence of at least twice that reported with placebo in short-term clinical studies include nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and sexual function disorders in males.1,53

Desvenlafaxine is principally metabolized by uridine diphosphoglucuronosyltransferase (UGT) isoenzymes and, to a lesser extent, by cytochrome P-450 (CYP) 3A4 isoenzyme.1,53 The drug does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, or 2D6 isoenzymes.1,53 Desvenlafaxine is not an inhibitor or inducer of CYP3A4.1,53

Desvenlafaxine is not a substrate or an inhibitor of the P-glycoprotein transporter in vitro.1,53

Drugs Metabolized by Hepatic Microsomal Enzymes

Concomitant use of desvenlafaxine with drugs primarily metabolized by CYP2D6 (e.g., desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) may result in higher peak plasma concentrations and total exposure of the substrate drug, which may lead to an increased risk of toxicity.1,53 Concurrent administration of desvenlafaxine 100 mg and desipramine, a CYP2D6 substrate, increased peak plasma concentrations and AUC of desipramine by approximately 25 and 17%, respectively; coadministration of desvenlafaxine 400 mg and desipramine increased peak plasma concentrations and AUC of desipramine by approximately 52 and 90%, respectively.1 The manufacturers state that when desvenlafaxine dosages of 100 mg daily or lower are used concomitantly with a CYP2D6 substrate, no dosage adjustment of the CYP2D6 substrate is needed.1,53 However, when desvenlafaxine dosages of 400 mg daily are used concurrently with a CYP2D6 substrate, dosage of the CYP2D6 substrate should be reduced by up to 50%.1,53

Desvenlafaxine does not inhibit or induce the CYP3A4 isoenzyme in vitro.1,53 Concurrent administration of desvenlafaxine 400 mg and midazolam, a CYP3A4 substrate, decreased AUC and peak plasma concentrations of midazolam by approximately 31 and 16%, respectively.1 The manufacturers state that no dosage adjustment is necessary when drugs mainly metabolized by CYP3A4 (e.g., midazolam) are used concomitantly with desvenlafaxine.1,53

No dosage adjustment of drugs metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole) is needed when used concomitantly with desvenlafaxine.1,53 Concurrent administration of desvenlafaxine 100 mg and tamoxifen did not substantially impact peak plasma concentrations or AUC of tamoxifen or its active metabolites (4-hydroxytamoxifen and endoxifen).1 Concurrent administration of desvenlafaxine 100 mg and aripiprazole did not substantially impact peak plasma concentrations or AUC of aripiprazole or its active metabolite (dehydroaripiprazole).1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 is a minor pathway for the metabolism of desvenlafaxine.1,53 Concomitant administration of ketoconazole, a CYP3A4 inhibitor, resulted in a 43% increase in AUC and an 8% increase in peak plasma concentrations of desvenlafaxine.1

Clinically important pharmacokinetic interactions are unlikely with inhibitors of CYP isoenzymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1.1,53

Drugs Affecting Hemostasis

Potential pharmacologic interaction (increased risk of bleeding) if used concurrently with antiplatelet or anticoagulant drugs (e.g., aspirin, nonsteroidal anti-inflammatory agents, warfarin).1,53 This increased risk of bleeding is potentially caused by the effect of desvenlafaxine on the release of serotonin by platelets.1,53

The manufacturers recommend carefully monitoring in patients receiving an antiplatelet or anticoagulant drug during initiation and discontinuance of desvenlafaxine therapy.1,53

Alcohol

In a clinical study, desvenlafaxine did not increase the impairment of mental and motor skills caused by alcohol.1,53 However, the manufacturers recommend avoiding concomitant alcohol consumption during desvenlafaxine therapy.1,53

Monoamine Oxidase Inhibitors

Concomitant use of SSRIs and SNRIs, including desvenlafaxine, with MAOIs increases the risk of serotonin syndrome.1,53 Concomitant use of desvenlafaxine with MAOIs (e.g. selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue) is contraindicated.1,53

At least 14 days should elapse between discontinuance of an MAOI intended to treat psychiatric disorders and initiation of desvenlafaxine, and at least 7 days should elapse between discontinuance of desvenlafaxine and initiation of an MAOI intended to treat psychiatric disorders.1,53

Do not initiate desvenlafaxine in patients receiving linezolid or IV methylene blue; if urgent treatment with linezolid or IV methylene blue is required in a patient receiving desvenlafaxine, stop desvenlafaxine and monitor for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or IV methylene blue (whichever comes first).1,53 Resume desvenlafaxine 24 hours after the last dose of linezolid or IV methylene blue.1,53

Serotonergic Drugs

Concomitant use of desvenlafaxine and other drugs affecting serotonergic neurotransmission (e.g., SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, St. John's wort [ Hypericum perforatum ]) increases the risk of serotonin syndrome.1,53 Monitor for serotonin syndrome if serotonergic agents are used concomitantly with desvenlafaxine.1,53 If serotonin syndrome occurs, consider discontinuation of desvenlafaxine and any concurrently administered serotonergic agents.1,53

Laboratory Tests

Due to a lack of specificity in screening tests, false-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients receiving desvenlafaxine.1,53 False-positive tests can be expected for several days following discontinuance of desvenlafaxine.1,53 Gas chromatography/mass spectrometry can be used for confirmatory testing to distinguish desvenlafaxine from PCP and amphetamine.1,53

Description

Desvenlafaxine, a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI), is an antidepressant.1,53 The drug is the principal active metabolite of venlafaxine.1,53

The exact mechanism of antidepressant action of desvenlafaxine has not been fully elucidated but appears to be associated with the drug's potentiation of serotonergic and noradrenergic activity in the CNS.1,4,5 Desvenlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake; however, inhibition of dopamine reuptake at concentrations that inhibit serotonin and norepinephrine reuptake appears unlikely in most patients.1,3,4,5 The drug does not inhibit monoamine oxidase (MAO) and has not demonstrated significant affinity for muscarinic cholinergic, H₁-histaminergic, α₁-adrenergic, dopaminergic, γ-aminobutyric acid (GABA), glutamate, and opiate receptors in vitro.1,3,4,5

The pharmacokinetics of desvenlafaxine are linear and dose proportional over a single-dose range of 50-600 mg (1-12 times the recommended dosage) per day.1,53 Following repeated once-daily dosing, steady state serum concentrations of desvenlafaxine are attained in approximately 4-5 days.1,53 Following oral administration of desvenlafaxine, the absolute oral bioavailability is about 80%.1,53 Peak plasma concentrations are increased approximately 16% when administered with a high-fat meal (800-1000 calories) compared to the fasted state, with no effect on the AUC.1,53 Desvenlafaxine is 30% protein-bound, which is independent of plasma concentrations.1,53 It is principally metabolized via conjugation by UGT isoenzymes and, to a lesser extent, through oxidation (by the cytochrome P-450 [CYP] 3A4 isoenzyme).1,53 Approximately 45% of a single oral dose of desvenlafaxine is eliminated unchanged in the urine at 72 hours; approximately 19% of the dose is excreted as the glucuronide metabolite, and less than 5% is excreted as the oxidative metabolite (N,O-didesmethylvenlafaxine).1,53

In female patients, peak plasma concentrations were approximately 26% higher compared to the reference population, with no substantial change in AUC.1,53 In geriatric patients 65-75 years of age, there was no substantial change in peak plasma concentrations, but AUC was increased approximately 32% compared to the reference population.1,53 In geriatric patients >75 years of age, peak plasma concentrations increased approximately 32%, and AUC increased 56% compared to the reference population.1,53 There were no clinically significant differences in desvenlafaxine exposure based on ethnicity (White, Black, Hispanic).1,53

Advice to Patients

• Risk of suicidality; advise patients, family, and caregivers to look for and immediately report emergence of suicidality, especially during the first few months of therapy and during periods of dosage adjustment.1,53
• Advise patients about the importance of reading the patient information before taking desvenlafaxine and each time the prescription is refilled.1,53
• Inform patients of potential risk of serotonin syndrome, particularly with concurrent use of 5-HT1 receptor agonists (also called triptans), tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John's Wort ( Hypericum perforatum ), and other serotonergic agents.1,53 Patients should immediately contact their clinician if signs and symptoms of serotonin syndrome develop.1,53
• Advise patients not to concurrently take other products containing desvenlafaxine or venlafaxine.1,53
• Instruct patients not to take desvenlafaxine with a MAOI or within 14 days of stopping the drug, and to allow at least 7 days after stopping desvenlafaxine before starting therapy with an MAOI.1,53
• Risk of discontinuance symptoms when switching from other antidepressants, including venlafaxine, to desvenlafaxine.1,53 Advise patients that tapering of the previous antidepressant may be necessary to minimize the risk of such symptoms.1,53
• Advise patients that they should have regular monitoring of blood pressure while taking desvenlafaxine.1,53
• Advise patients, their families, and caregivers to observe desvenlafaxine-treated patients for signs of activation of mania/hypomania.1,53
• Advise patients to notify their clinician if they develop any allergic signs or symptoms during therapy (e.g., rash, hives, swelling, difficulty breathing).1,53
• Risk of cognitive and motor impairment; advise patients to exercise caution while operating hazardous machinery, including automobile driving, until they are reasonably certain that desvenlafaxine therapy does not adversely affect their ability to engage in such activities.1,53
• Risk of sexual dysfunction in male and female patients; advise patients to discuss any changes in sexual function and potential management strategies with their clinician.1,53
• Advise patients to avoid alcohol during desvenlafaxine therapy.1,53
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1,53
• Advise patients about the risk of bleeding associated with concomitant use of desvenlafaxine and aspirin, nonsteroidal anti-inflammatory agents, other antiplatelet drugs, warfarin, or other anticoagulants.1,53
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,53 Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to desvenlafaxine during pregnancy.1,53
• Advise patients not to stop taking desvenlafaxine without first talking with their clinician.1,53 Advise patients that discontinuance effects may occur when stopping the drug.1,53
• Inform patients that they may notice an inert matrix tablet passing in the stool or via colostomy, and that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.1,53
• Inform patients of other important precautionary information.1,53

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Wyeth Laboratories Inc (a subsidiary of Pfizer). Pristiq^® (desvenlafaxine succinate) extended-release tablets prescribing information. Philadelphia, PA; 2024 June.

3. DeMartinis NA, Yeung PP, Entsuah R et al. A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. J Clin Psychiatry . 2007; 68:677-88. [PubMed 17503976]

4. Deecher DC, Beyer CE, Johnston G et al. Desvenlafaxine succinate: a new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther . 2006; 318:657-65. [PubMed 16675639]

5. Septien-Velez L, Pitrosky B, Padmanabhan SK et al. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol . 2007; 22:338-47.

10. Speroff L, Gass M, Constantine G et al for the Study 315 Investigators. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol . 2008; 111:77-87. [PubMed 18165395]

11. Wyrwich KW, Spratt DI, Gass M et al. Identifying meaningful differences in vasomotor symptoms among menopausal women. Menopause . 2008; 15 (4 Part 1): 698-705. [PubMed 18369313]

19. Liebowitz MR, Yeung PP, Entsuah R. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder. J Clin Psychiatry . 2007; 68:1663-72. [PubMed 18052559]

25. Archer DF, Dupont CM, Constantine GD et al. for the Study 319 investigators. Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol . 2009; 200:238.e1-238.e10.

26. Archer DF, Seidman L, Constantine GD et al. A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause. Am J Obstet Gynecol . 2009; 200:172.e1-172.e10.

29. Pinkerton JV, Stovall DW, Kightlinger RS. Advances in the treatment of menopausal symptoms. Womens Health (Lond Engl) . 2009; 5:361-384; quiz 383-4.

30. Lilue M, Palacios S. [Non-hormonal treatment for vasomotor symptoms during menopause: role of desvenlafaxine]. Ginecol Obstet Mex . 2009; 77:475-81. [PubMed 19902676]

31. Carroll DG, Kelley KW. Use of antidepressants for management of hot flashes. Pharmacotherapy . 2009; 29:1357-74. [PubMed 19857151]

32. Lewis V. Undertreatment of menopausal symptoms and novel options for comprehensive management. Curr Med Res Opin . 2009; 25:2689-98. [PubMed 19775194]

33. Kontos M, Agbaje OF, Rymer J et al. What can be done about hot flushes after treatment for breast cancer?. Climacteric . 2010; 13:4-21. [PubMed 20067430]

34. Seo H-J, Sohi MS, Patkar AA et al. Desvenlafaxine succinate: a newer antidepressant for the treatment of depression and somatic symptoms. Postgrad Med . 2010; 122:125-38. [PubMed 20107296]

35. Anon. Desvenlafaxine for depression. Med Lett Drugs Ther . 2008; 50:37-8.

37. Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA . 2006; 295:2057-71. [PubMed 16670414]

38. Sopko MA, Ehret MJ, Grgas M. Desvenlafaxine: another “me too” drug?. Ann Pharmacotherapy . 2008; 42:1439-46.

41. Institute for Safe Medication Practices (ISMP). ISMP list of confused drug names. ISMP; 2023.

42. Rosenthal JZ, Boyer P, Vialet C, Hwang E, Tourian KA. Efficacy and safety of desvenlafaxine 50 mg/d for prevention of relapse in major depressive disorder: a randomized controlled trial. J Clin Psychiatry . 2013;74(2):158-166.

49. Iwata N, Tourian K, Hwang E, et al. Efficacy and safety of desvenlafaxine 25 and 50 mg/day in a randomized, placebo-controlled study of depressed outpatients. J Psychiatr Pract. 2013;19(1):5-14.

50. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010.; 167 (suppl). [Web]

51. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, 2022. [Web]

52. NAMS Position Statement. The 2023 nonhormone therapy position statement of the North American Menopause Society. Menopause . 2023;30(6): 573-590.

53. Sun Pharmaceuticals. Desvenlafaxine extended-release tablets prescribing information. Cranbury, NJ; 2023 Aug. [Web]

54. American Psychological Association. (2019). Clinical practice guideline for the treatment of depression across three age cohorts. Retrieved from http://www.apa.org/depression-guideline

55. Drugs for depression. Med Lett Drugs Ther. 2023 Dec 11;65(1691):193-200. doi: 10.58347/tml.2023.1691a. PMID: 38133585.