Desvenlafaxine Succinate

Pronunciation

Pronunciation: des-VEN-la-FAX-een SUX-i-nate
Class: SNRI

Trade Names

Pristiq
- Tablets, ER 50 mg
- Tablets, ER 100 mg

Pharmacology

Potentiates serotonin and norepinephrine in the CNS.

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Pharmacokinetics

Absorption

Absolute bioavailability after oral administration is about 80%. T max is about 7.5 h. Steady state reached in 4 to 5 days.

Distribution

Plasma protein binding is about 30%. Vd at steady state following IV administration is 3.4 L/kg, indicating distribution into nonvascular compartment.

Metabolism

Primarily by conjugation (UGT isoforms) and to a lesser extent through oxidative metabolism (CYP3A4).

Elimination

After oral administration, about 45% is excreted unchanged in the urine within 72 h, approximately 19% excreted as the glucuronide, and less than 5% as the oxidative metabolites. Mean half-life is 11 h.

Special Populations

Renal Function Impairment

Elimination is correlated with CrCl. The AUC increases about 42% in patients with mild renal impairment, about 46% in those with moderate renal impairment, about 108% in those with severe renal impairment, and about 116% in ESRD. The mean terminal half-life is prolonged from 11.1 h in control subjects to about 13.5, 15.5, 17.6, and 22.8 h in those with mild, moderate, severe, and ESRD, respectively. Less than 5% of the drug is cleared during standard 4-h hemodialysis.

Hepatic Function Impairment

Average AUC is increased by about 31% and 35% in patients with moderate and severe hepatic impairment, respectively. Cl is decreased about 20% and 36% in patients with moderate and severe hepatic impairment, respectively. The mean half-life increased from 10 h in healthy subjects to 13 and 14 h in patients with moderate and severe hepatic impairment, respectively. No dosage adjustment is needed in the starting dose for patients with hepatic impairment.

Elderly

There is an increase in the AUC and C max of about 55% and 32%, respectively, in patients older than 75 yr of age compared with patients 18 to 45 yr of age. Patients 65 to 75 yr of age had a 32% increase in AUC but no change in C max compared with patients 18 to 45 yr of age.

Gender

There is an increase in the AUC and C max of about 10% and 25%, respectively, in women compared with men; however, no dosage adjustment is needed.

Race

Race has no apparent effect on pharmacokinetics.

Indications and Usage

Treatment of major depressive disorder (MDD).

Contraindications

Concomitant use with MAOIs; hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO 50 mg once daily. No benefit has been demonstrated at dosages of more than 50 mg/day.

Renal function impairment
Adults

PO

Severe renal impairment (CrCl less than 30 mL/min) or ESRD

50 mg every other day. Do not give supplemental doses after dialysis.

General Advice

  • Can be taken without regard to meals.
  • When discontinuing therapy, gradually reduce the dose.
  • Periodically reassess to determine the need for continued treatment.
  • Tablets should be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Aspirin, NSAIDs, warfarin

Risk of bleeding may be increased.

CNS-active agents (eg, alcohol)

Coadminister with caution. Patients should avoid alcohol consumption while taking desvenlafaxine.

CYP3A4 inhibitors (eg, ketoconazole)

Desvenlafaxine plasma concentrations may be elevated.

Drugs metabolized by CYP2D6 (eg, desipramine)

Plasma concentrations may be elevated by desvenlafaxine.

Drugs metabolized by CYP3A4 (eg, midazolam)

Plasma concentrations may be decreased by desvenlafaxine.

MAOIs

Serious, even fatal, reactions may occur. Do not use desvenlafaxine with MAOIs or within 14 days of MAOI use. Allow at least 7 days after stopping desvenlafaxine before starting MAOIs.

Serotonergic drugs (eg, linezolid, metoclopramide, sibutramine, SNRIs, SSRIs, tramadol, trazodone, triptans)

Risk of life-threatening serotonin syndrome may be increased.

St. John's wort

Serotonin syndrome may occur.

Tryptophan

Concurrent use is not recommended.

Venlafaxine-containing drugs

Desvenlafaxine is the active metabolite of venlafaxine. Do not coadminister drugs containing venlafaxine.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Palpitations (3%); hot flush, increased BP, tachycardia (2%); orthostatic hypotension, syncope (less than 2%); coronary occlusion requiring revascularization, MI, myocardia ischemia (rare).

CNS

Headache (29%); dizziness (16%); insomnia (15%); somnolence (12%); fatigue (11%); tremor (9%); decreased libido in men (6%); anxiety (5%); abnormal dreams (4%); feeling jittery, paresthesia (3%); asthenia, disturbance in attention, irritability, nervousness (2%); convulsion, depersonalization, extrapyramidal disorder, hypomania (less than 2%).

Dermatologic

Hyperhidrosis (21%); rash (2%).

EENT

Mydriasis (6%); blurred vision (4%); dysgeusia, tinnitus (2%); epistaxis (less than 2%).

GI

Nausea (41%); dry mouth (25%); constipation (14%); diarrhea (11%); vomiting (9%).

Genitourinary

Erectile dysfunction (11%); anorgasmia (men, 8%; women, 3%); proteinuria (8%); delayed ejaculation (7%); ejaculation disorder (5%); abnormal orgasm in men (3%); ejaculation failure, sexual dysfunction, urinary hesitation (2%).

Hypersensitivity

Hypersensitivity (less than 2%).

Lab Tests

Increased total cholesterol (10%); increased fasting triglycerides (6%); increased LDL (2%); abnormal liver function, increased blood prolactin (less than 2%).

Metabolic-Nutritional

Decreased appetite (10%); decreased weight (2%).

Respiratory

Yawning (4%).

Miscellaneous

Chills (4%).

Precautions

Warnings

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders. Appropriately monitor and closely observe patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescriber. Desvenlafaxine is not approved for use in children.


Monitor

Closely observe patient for clinical worsening, suicidality, or unusual changes in behavior during initial few months of therapy or when increasing or decreasing the dose. Monitor patients with elevated IOP or acute narrow-angle glaucoma. Consider monitoring serum lipids. Monitor BP regularly.


Pregnancy

Category C . Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Consider potential risks and benefits when treating women during the third trimester.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Consider the possibility of reduced renal Cl when determining the dose. Systolic orthostatic hypotension occurs more frequently in patients 65 yr of age and older.

Renal Function

Dosage adjustment is recommended.

Abnormal bleeding

Risk of bleeding events, ranging from ecchymosis to life-threatening hemorrhages, may be increased.

CV

Sustained increases in BP may occur. Control preexisting hypertension before starting treatment. Use with caution in patients with CV disease, or cerebrovascular or preexisting hypertension.

Discontinuation of treatment

When discontinuing treatment, a gradual reduction in dosage rather than abruptly stopping therapy is recommended.

Hyponatremia

Hyponatremia as a result of SIADH may occur. Elderly patients and patients taking diuretics or who are otherwise volume depleted may be at increased risk.

Interstitial lung disease and eosinophilic pneumonia

Because these conditions have been associated with venlafaxine, the parent drug of desvenlafaxine, consider the possibility that these adverse reactions may occur.

Mania/Hypomania

Activation of mania/hypomania has been reported. Use with caution in patients with a history of mania or hypomania.

Narrow-angle glaucoma

Mydriasis may occur.

Screening for bipolar disorder

A major depressive episode may be the initial presentation of bipolar disorder. 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. Screen patients with depression for risk of bipolar disorder prior to initiating therapy with an antidepressant.

Seizure

Use with caution in patients with a history of seizure disorder.

Serotonin syndrome and NMS-like reactions

Potentially life-threatening serotonin syndrome or NMS-like reactions, including mental status changes, may occur.

Serum cholesterol and triglyceride elevations

Dose-related elevations in fasting serum total cholesterol, LDL cholesterol, and triglycerides may occur. Use with caution in patients with lipid metabolism disorders.

Overdosage

Symptoms

Agitation, constipation, diarrhea, dizziness, dry mouth, headache, nausea, paresthesia, tachycardia, vomiting.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patients to look for emergence of suicidality, especially early during treatment and when the dose is increased or decreased.
  • Advise patients to observe for signs of activation of mania/hypermania.
  • Advise patients not to stop taking desvenlafaxine without talking with health care provider.
  • Caution patients about driving or operating hazardous machinery until they are certain that their ability to engage in such activities is not impaired.
  • Advise patients to notify health care provider if they develop allergic reactions, such as difficulty breathing, hives, rash, or swelling.
  • Caution patients about concomitant use of aspirin, NSAIDs, warfarin, or other drugs affecting coagulation because they may be at increased risk of bleeding.
  • Inform patients that they may notice an inert matrix tablet in their stool and that this is normal and not cause for concern.
  • Advise patients to avoid alcohol while taking desvenlafaxine.

Copyright © 2009 Wolters Kluwer Health.

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