desvenlafaxine (Rx)

Adverse drug reactions (ADRs) shown occur with 50 mg/day dosage at rate higher than seen with placebo

>10%

Nausea (22-41%)

Dry mouth (11-25%)

Hyperhidrosis (10-21%)

Dizziness (10-16%)

Insomnia (9-15%)

Constipation (9-14%)

Somnolence (4-12%)

Fatigue (7-10%)

1-10%

Increased total cholesterol of ≥50 mg/dL and an absolute value of ≥261 mg/dL (3-10%)

Decreased appetite (5-10%)

Vomiting (3-9%)

Tremor (2-9%)

Anorgasmia (3-8%)

Ejaculation delayed (1-7%)

Libido decreased (3-6%)

Triglycerides, fasting ≥327 mg/dL (2-6%)

Mydriasis (2-6%)

Vertigo (2-5%)

Anxiety (3-5%)

Blurred vision (3-4%)

Chills (1-4%)

Yawning (1-4%)

Abnormal dreams (2-3%)

Feeling jittery (1-3%)

Orgasm abnormal (1-3%)

Nervousness (<2%)

Tachycardia (<2%)

Asthenia (<2%)

Weight increased, liver function test abnormal, blood prolactin increased (<2%)

Musculoskeletal stiffness (<2%)

Syncope, convulsion, dystonia (<2%)

Depersonalization, bruxism (<2%)

Urinary retention (<2%)

Rash, alopecia, photosensitivity reaction, angioedema (<2%)

Urinary hesitation (1-2%)

Ejaculation failure (1-2%

Sexual dysfunction (1-3%)

Tinnitus (1-2%)

Dysgeusia (1-2%)

Hot flush (1-2%)

Blood pressure increased (1-2%)

Increased LDL ≥50 mg/dL and an absolute value of ≥190 mg/dl (1-2%)

Frequency Not Defined

Ischemic cardiac events in patients with multiple underlying cardiac risk factors

Gastrointestinal (GI) bleeding, hallucinations, photosensitivity reactions and severe cutaneous reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) have occurred with other serotonin-norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs)

Suicidal thoughts and behaviors in adolescents and young adults

Hyponatremia

Interstitial lung disease and eosinophilic pneumonia

Serotonin syndrome

Elevated blood pressure

Abnormal bleeding

Narrow-angle glaucoma

Activation of mania or hypomania

Discontinuance syndrome

Seizure

Postmarketing Reports

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.

Contraindications

Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine formulation

Coadministration with serotonergic drugs

• Coadministration with MAOIs increases risk of serotonin syndrome
• Use of MAOIs concomitantly within 14 days before initiating desvenlafaxine or within 7 days after discontinuing desvenlafaxine
• Symptoms include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome (NMS), seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma
• Starting desvenlafaxine in patient being treated with linezolid or IV methylene blue is contraindicated because of increased risk of serotonin syndrome
• If linezolid or IV methylene blue must be administered, discontinue desvenlafaxine immediately and monitor for central nervous system (CNS) toxicity; therapy may be resumed 24 hours after last linezolid or methylene blue dose or after 2 weeks of monitoring, whichever comes first

Cautions

Suicidality; monitor for clinical worsening and suicide risk (especially in children, adolescents, and young adults aged 18-24 years), during early phases of treatment and alterations in dosages

Neonates exposed to SNRIs or SSRIs late in 3rd trimester of pregnancy have developed complications necessitating prolonged hospitalization, respiratory support, and tube feeding

Control hypertension before initiating treatment; monitor blood pressure regularly during treatment; if sustained hypertension is observed, consider dosage reduction or discontinuance

Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy; avoid use of antidepressants, including desvenlafaxine, in patients with untreated anatomically narrow angles

Use caution in patients with history of seizure disorders

Screen patients for bipolar disorder; risk of mixed or manic episodes is increased in patients treated with antidepressants

May precipitate shift to mania or hypomania in patients with bipolar disorder; avoid monotherapy in patients with bipolar disorder; screen for bipolar disorder patients presenting with depressive symptoms

Cardiovascular, cerebrovascular or lipid metabolism disorders; monitor patients who have history of or are at risk for these disorders

Monitor serum lipids periodically; risk of elevations in fasting serum total cholesterol, low-density lipoprotein (LDL) and triglycerides is increased

Hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH); cases of serum sodium ≤110 mmol/L have been reported; monitor patients who are taking diuretics or at risk for volume depletion

Rare reports of interstitial lung disease and eosinophilic pneumonia; monitor patients for progressive dyspnea, cough, or chest discomfort

Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy

May impair congnitive abilities; use caution operating heavy machinery

A gradual reduction in dosage rather than abrupt cessation recommended; monitor for discontinuation symptoms; adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures

Serotonin syndrome

• Consider risk of serotonin syndrome if administered concomitantly with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort
• Serotonin syndrome or NMS-like reactions may occur; discontinue and initiate supportive therapy; closely monitor patients concomitantly receiving triptans, antipsychotics, or serotonin precursors
• Serotonin syndrome signs and symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (eg, nausea, vomiting, diarrhea)
• Neonates exposed to SNRIs or SSRIs late in 3rd trimester of pregnancy have developed complications necessitating prolonged hospitalization, respiratory support, and tube feeding
• Monitor for the emergence of serotonin syndrome
• Discontinue treatment with desvenlafaxine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment
• If concomitant use of desvenlafaxine with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms See Contraindications

Drug interactions overview

• Concomitant use of desvenlafaxine increases peak plasma concentration and AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drugs
• False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine

• Risk of bleeding

  • SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage
  • Concomitant use of aspirin, NSAIDs, warfarin, other anticoagulants, or other drugs known to affect platelet function may add to this risk
  • For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing therapy

Pregnancy

Pregnancy exposure registry 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

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

Exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage

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

Lactation

Available limited data from published literature show low levels of desvenlafaxine in human milk, and have not shown adverse reactions in breastfed infants

There are no data on the effects of desvenlafaxine on milk production

Consider the developmental and health benefits of breastfeeding 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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Potent SNRI; major active metabolite of venlafaxine

Absorption

Bioavailability: 80%

Peak plasma time: 7.5 hr

Ingestion of a high-fat meal (800-1000 calories) increased desvenlafaxine peak plasma concentration about 16% and had no effect on AUC

Distribution

Protein bound: 30%

Vd: 3.4 L/kg

Metabolism

Primary: Conjugation (UDP-glucuronosyltransferase isoform mediated)

Minor: CYP3A4 oxidative metabolism (N-demethylation)

Enzymes inhibited: CYP2D6 (minimally)

Elimination

Half-life: 11 hr (prolonged in renal or hepatic dysfunction)

Dialyzable: No

Excretion, unchanged drug: Urine (45%)

Excretion, metabolite: 19% (glucuronide); <5% (oxidative metabolite [N,O-didesmethylvenlafaxine])

Oral Administration

Take 1 tablet at about the same time each day

Take either with or without food

Swallow tablets whole, with fluid

Do not divide, crush, chew, or dissolve tablets

Avoid drinking alcohol while taking dose

Storage

Tablets: Store at 20- 25°C (68-77°F); excursions permitted to 15-30°C (59- 86°F)