Brand name: Pristiq
Drug class: Selective Serotonin- and Norepinephrine-reuptake Inhibitors
- Serotonin-reuptake Inhibitors
- SNRIs
Chemical name: RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol
Molecular formula: C₁₆H₂₅NO₂•C₄H₆O₄•H₂O
CAS number: 386750-22-7

Introduction

A selective serotonin- and norepinephrine-reuptake inhibitor (SNRI); an antidepressant.

Uses for Desvenlafaxine

Major Depressive Disorder

Treatment of major depressive disorder in adults.

Efficacy of long-term use (i.e., >8 weeks) not established by controlled studies. If desvenlafaxine is used for extended periods, the need for continued therapy should be reassessed periodically.

Desvenlafaxine Dosage and Administration

General

• Allow at least 14 days to elapse between discontinuance of an MAO inhibitor and initiation of desvenlafaxine and at least 7 days to elapse between discontinuance of desvenlafaxine and initiation of an MAO inhibitor.

• If switching from another antidepressant (including venlafaxine) to desvenlafaxine, may be necessary to taper dosage of the previous antidepressant to minimize discontinuance symptoms.

• Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments. (See Worsening of Depression and Suicidality Risk under Cautions.)

• Avoid abrupt discontinuance. Taper dosage gradually and monitor for withdrawal symptoms. If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage, then resume more gradual dosage reductions. (See Worsening of Depression and Suicidality Risk and also see Withdrawal of Therapy under Cautions.)

• If used during pregnancy, consider cautiously tapering dosage during third trimester prior to delivery. (See Pregnancy under Cautions.)

• Sustained therapy may be required; periodically reassess need for continued therapy.

Administration

Oral Administration

Administer orally with or without food at approximately the same time each day.

Swallow extended-release tablets whole with fluid; do not divide, crush, chew, or dissolve.

Dosage

Available as desvenlafaxine succinate; dosage expressed in terms of desvenlafaxine.

Adults

Major Depressive Disorder

Oral

50 mg once daily. Although efficacy established at dosages of 50–400 mg once daily in clinical studies, no additional benefit observed with dosages >50 mg once daily; adverse effects and discontinuances were more frequent at higher dosages.

Optimum duration not established; may require several months or longer of sustained antidepressant therapy. Long-term efficacy (i.e., >8 weeks) of desvenlafaxine at a dosage of 50 mg once daily not studied. Periodically reassess need for continued therapy.

Special Populations

Hepatic Impairment

Oral

Initially, 50 mg once daily. Dosage increases to >100 mg daily not recommended.

Renal Impairment

Oral

Mild renal impairment (Cl_cr 50–80 mL/minute): No dosage adjustment needed.

Moderate renal impairment (Cl_cr 30–50 mL/minute): 50 mg once daily. Do not increase dosage.

Severe renal impairment (Cl_cr< 30 mL/minute) or end-stage renal disease: 50 mg every other day. Do not increase dosage and do not give supplemental doses after dialysis.

Geriatric Patients

No specific dosage recommendations at this time, but consider possibility of age-related decreases in renal function when selecting dosage. May administer drug every other day if poorly tolerated.

Related/similar drugs

sertraline, trazodone, Lexapro, Zoloft, citalopram, Wellbutrin, Cymbalta

Cautions for Desvenlafaxine

Contraindications

• Known hypersensitivity to desvenlafaxine, venlafaxine, or any ingredient in the formulation.

• Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor. Allow at least 7 days to elapse after discontinuing desvenlafaxine before initiating an MAO inhibitor. (See Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs. (See Boxed Warning and also see Pediatric Use under Cautions.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

Appropriately monitor and closely observe patients receiving desvenlafaxine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality. Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of the patient’s presenting symptoms. If decision is made to discontinue drug therapy, taper desvenlafaxine dosage as rapidly as is feasible but consider risks of abrupt discontinuance. (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.

Bipolar Disorder

May unmask bipolar disorder. (See Activation of Mania/Hypomania under Cautions.)Desvenlafaxine is not approved for use in treating bipolar depression.

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.

Other Warnings and Precautions

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions reported during concurrent therapy with SSRIs or SNRIs and other serotonergic drugs (e.g., 5-HT₁ receptor agonists [“triptans”]), drugs that impair serotonin metabolism (e.g., MAO inhibitors), or antipsychotics or other dopamine antagonists. (See Contraindications under Cautions and see Interactions.)

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

Severe serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

Monitor patients receiving desvenlafaxine for the development of serotonin syndrome or NMS-like signs and symptoms. If serotonin syndrome or NMS signs and symptoms occur, discontinue desvenlafaxine and any concurrently administered serotonergic or antidopaminergic agents, including antipsychotic agents, and initiate supportive and symptomatic treatment.

Risk of Sustained Hypertension

Sustained hypertension (i.e., treatment-emergent increases in supine DBP ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits) reported; potential adverse consequences. Elevated BP requiring immediate treatment also reported.

Control preexisting hypertension before initiating desvenlafaxine therapy and regularly monitor BP during therapy. Exercise caution in patients with preexisting hypertension or other underlying conditions that may be compromised by increases in BP. If sustained increases in BP occur, consider desvenlafaxine dosage reduction or discontinuance.

Abnormal Bleeding

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. Possible increased risk of bleeding with SSRIs and SNRIs, including desvenlafaxine; events ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Concurrent administration of aspirin, NSAIAs, warfarin, and other anticoagulants may increase risk. (See Drugs Affecting Hemostasis under Interactions and also see Advice to Patients.)

Mydriasis

Mydriasis reported. Monitor patients with elevated IOP or at risk of angle-closure glaucoma.

Activation of Mania/Hypomania

Possible activation of mania and hypomania; use with caution in patients with personal or family history of mania or hypomania. (See Bipolar Disorder under Cautions.)

Cardiovascular/Cerebrovascular Disease

Increases in BP and small increases in heart rate reported; use with caution in patients with cardiovascular, cerebrovascular, or lipid metabolism disorders.

Effects on Cholesterol and Lipoproteins

Dose-dependent, possibly clinically significant increases in fasting serum total cholesterol, LDL cholesterol, and triglycerides reported; consider measuring serum lipid concentrations during therapy.

Withdrawal of Therapy

Withdrawal effects reported with abrupt discontinuance or dosage reduction; reactions included dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis and occurred more frequently with longer duration of therapy. Withdrawal effects also reported upon discontinuance of other SNRIs and SSRIs, particularly when abrupt; events generally are self-limiting, but may be serious.

If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage, then resume more gradual dosage reductions.

Seizures

Seizures reported in premarketing clinical studies. Desvenlafaxine has not been studied in patients with a history of seizures; use with caution in such patients.

Hyponatremia/SIADH

Possible hyponatremia or SIADH; use with caution in patients who are volume-depleted, elderly, or taking diuretics. Initiate appropriate medical intervention and consider drug discontinuance in patients with symptomatic hyponatremia.

Concomitant Administration of Drugs Containing Desvenlafaxine and Venlafaxine

Do not use products containing desvenlafaxine and products containing venlafaxine concomitantly with Pristiq (desvenlafaxine succinate); desvenlafaxine is the principal active metabolite of venlafaxine. (See Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (parent drug of desvenlafaxine) reported rarely; consider possibility in patients treated with desvenlafaxine who present with progressive dyspnea, cough, or chest discomfort. Promptly evaluate patients with these symptoms and consider discontinuance of desvenlafaxine.

Specific Populations

Pregnancy

Category C.

Possible complications, sometimes severe and requiring prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in neonates exposed to SNRIs or SSRIs late in the third trimester; may arise immediately upon delivery.

Carefully consider the potential risks and benefits of treatment when used during the third trimester of pregnancy. Consider cautiously tapering dosage during the third trimester prior to delivery.

Lactation

Distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and effectiveness not established in pediatric patients <18 years of age. Possible adverse effects on weight, height, appetite, BP, and serum cholesterol concentrations reported in pediatric patients receiving venlafaxine, the parent drug of desvenlafaxine.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others). However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of desvenlafaxine in a child or adolescent for any clinical use. (See Suicidality in the Boxed Warning and see Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

No overall differences in safety or efficacy observed relative to younger adults, but increased sensitivity cannot be ruled out. Consider possible reduced renal clearance of the drug in geriatric patients. (See Dosage and Administration: Special Populations and see Absorption: Special Populations, under Pharmacokinetics.)

Higher incidence of systolic orthostatic hypotension reported in patients ≥65 years of age.

Clinically important hyponatremia reported in geriatric patients. (See Hyponatremia/SIADH under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo. (See Suicidality in the Boxed Warning and see Worsening of Depression and Suicidality Risk under Cautions.)

Hepatic Impairment

Increased mean elimination half-life in patients with moderate and severe hepatic impairment compared with healthy individuals and patients with mild hepatic impairment. (See Hepatic Impairment under Dosage and Administration and see Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Decreased clearance in patients with moderate or severe renal impairment or end-stage renal disease; adjust dosage. (See Renal Impairment under Dosage and Administration and see Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and sexual function disorders in males (e.g., anorgasmia, decreased libido, abnormal orgasm, delayed ejaculation, erectile dysfunction, ejaculation disorder, ejaculation failure).

Drug Interactions

Principally metabolized via conjugation by UGT isoenzymes; oxidation via CYP3A4 isoenzyme is a minor metabolic pathway. Minimally inhibits CYP2D6; does not inhibit CYP 1A2, 2A6, 2C8, 2C9, or 2C19 isoenzymes; did not inhibit or induce CYP3A4 in vitro (see Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions).

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

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP2D6: Potential pharmacokinetic interaction (increased CYP2D6 substrate plasma concentrations).

Drugs metabolized by CYP3A4: Potential pharmacokinetic interaction (reduced exposure to CYP3A4 substrate). Although no inhibition or induction of CYP3A4 observed in vitro, AUC and peak plasma concentrations of CYP3A4 substrate decreased with concomitant administration of desvenlafaxine in one study.

Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9, or 2C19 isoenzymes: Pharmacokinetic interaction unlikely.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma desvenlafaxine concentrations).

Inhibitors of CYP isoenzymes 1A1, 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 2E1: Clinically important pharmacokinetic interaction is unlikely.

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions) with serotonergic drugs. Avoid concomitant use or exercise caution. If serotonin syndrome or NMS occurs, immediately discontinue desvenlafaxine and any concurrently administered antidopaminergic or serotonergic agents and initiate supportive and symptomatic treatment. (See Specific Drugs under Interactions and see Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

Drugs Affecting Hemostasis

Potential pharmacologic interaction (increased risk of bleeding) if used concurrently with drugs that affect coagulation or bleeding; use with caution. (See Abnormal Bleeding under Cautions.)

Drugs that are Substrates or Inhibitors of P-glycoprotein Transport System

Pharmacokinetic interaction unlikely.

CNS-active Drugs

Potential interactions not systematically evaluated to date; use with caution.

Electroconvulsive Therapy

Risks and/or benefits of combined use of electroconvulsive therapy and desvenlafaxine not evaluated.

Specific Drugs

Desvenlafaxine Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is about 80%.

Peak plasma concentrations achieved about 7.5 hours after oral administration.

In women, peak plasma concentrations and AUC were approximately 25 and 10% higher, respectively, than age-matched men, but no dosage adjustment needed.

Food

Peak plasma concentration was increased about 16% in the fed state compared with fasting, but AUCs were similar; difference not clinically important.

Special Populations

In healthy geriatric individuals 65–75 years of age, there was no change in peak plasma concentrations, but AUC was increased approximately 32% compared with subjects 18–45 years of age. In geriatric individuals >75 years of age, peak plasma concentrations increased approximately 32%, and AUC increased 55% compared with subjects 18–45 years of age.

Distribution

Extent

Distributed into milk.

Plasma Protein Binding

30%; plasma protein binding of desvenlafaxine is independent of plasma concentrations.

Elimination

Metabolism

Principally metabolized via conjugation by UGT isoenzymes; oxidation via CYP3A4 isoenzyme is a minor metabolic pathway.

Elimination Route

Approximately 45% of a single oral dose is eliminated unchanged in 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) in urine.

Half-life

Mean elimination half-life is approximately 11 hours.

Special Populations

In patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, average AUC was increased by approximately 31 and 35%, respectively compared with healthy individuals; in patients with mild hepatic impairment (Child-Pugh class A), average AUC values were similar to those in healthy subjects (<5% difference). In patients with moderate and severe hepatic impairment, systemic clearance was decreased by approximately 20 and 36%, respectively, compared with healthy individuals. In patients with mild hepatic impairment, systemic clearance was comparable to that in healthy individuals. Half-life was 13 and 14 hours in patients with moderate and severe hepatic impairment, respectively; half-life in patients with mild hepatic impairment was similar to that in healthy individuals.

In patients with renal impairment, elimination was correlated with Cl_cr. AUC was increased about 42% in mild renal impairment (24-hour Cl_cr: 50–80 mL/minute), about 56% in moderate renal impairment (24-hour Cl_cr: 30–50 mL/minute), about 108% in severe renal impairment (24-hour Cl_cr: ≤30 mL/minute), and about 116% in end-stage renal disease subjects, compared with healthy, age-matched control subjects. The mean terminal half-life was prolonged from 11.1 hours in the control subjects to approximately 13.5, 15.5, 17.6, and 22.8 hours in mild, moderate, and severe renal impairment, and end-stage renal disease subjects, respectively. Less than 5% of the drug in the body was cleared during a standard 4-hour hemodialysis procedure.

Stability

Storage

Oral

Extended-release Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Desvenlafaxine is the principal active metabolite of venlafaxine and is pharmacologically related to duloxetine, another SNRI.

• Exact mechanism of antidepressant action has not been fully elucidated but appears to be associated with potentiation of serotonergic and noradrenergic activity in the CNS.

• 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.

• Desvenlafaxine does not inhibit MAO and has not demonstrated substantial affinity for muscarinic cholinergic, H₁-histaminergic, α₁-adrenergic, dopaminergic, GABA, glutamate, and opiate receptors in vitro.

Advice to Patients

• Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment. FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.

• Importance of informing patients of potential risk of serotonin syndrome and neuroleptic malignant syndrome (NMS)-like reactions, particularly with concurrent use of desvenlafaxine and 5-HT₁ receptor agonists (also called triptans), tramadol, tryptophan, other serotonergic agents, or antipsychotic agents. Importance of immediately contacting clinician if signs and symptoms of these syndromes develop (e.g., restlessness, hallucinations, loss of coordination, fast heart beat, increased body temperature, muscle stiffness, increased BP, diarrhea, coma, nausea, vomiting, confusion).

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular, cerebrovascular, or lipid metabolism disorders; glaucoma) or personal or family history of suicidality or bipolar disorder.

• Importance of advising patients about the risk of bleeding associated with concomitant use of desvenlafaxine with aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.

• Importance of advising patients not to concurrently take other products containing desvenlafaxine or venlafaxine.

• Importance of instructing patients not to take desvenlafaxine with an MAO inhibitor or within 14 days of stopping the drug, and to allow 7 days after stopping desvenlafaxine before starting therapy with an MAO inhibitor.

• Importance of advising patients that they should have regular BP monitoring while taking desvenlafaxine.

• Importance of advising patients with raised IOP or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) that mydriasis has been reported with desvenlafaxine and that they should be monitored.

• Importance of advising patients, their families, and caregivers to observe desvenlafaxine-treated patients for signs of activation of mania/hypomania.

• Importance of advising patients that elevations in total cholesterol, LDL, and triglycerides may occur; measurement of lipid concentrations may be considered.

• Importance of advising patients to notify their clinician if they develop any allergic signs or symptoms during therapy (e.g., rash, hives, swelling, difficulty breathing).

• Risk of cognitive and motor impairment; importance of exercising caution while operating hazardous machinery, including automobile driving, until patients are reasonably certain that desvenlafaxine therapy does not adversely affect their ability to engage in such activities.

• Importance of avoiding alcohol during desvenlafaxine therapy.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients that it usually takes several weeks of antidepressant therapy before they will start to feel better. Advise patients not to stop taking the drug if they do not feel the results right away.

• Importance of advising patients not to stop taking desvenlafaxine without first talking with their clinician. Importance of patients being aware that discontinuance effects may occur when stopping desvenlafaxine or when switching from another antidepressant to desvenlafaxine.

• Importance of informing patients to swallow desvenlafaxine extended-release tablets whole, and not to crush, cut, chew, or dissolve the tablets.

• Importance of informing 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

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