Venlafaxine

— THERAPEUTIC CATEGORIES —
  • Mood disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Venlafaxine Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Venlafaxine (as HCl) 25mg, 37.5mg, 50mg, 75mg, 100mg; scored tabs.

    Pharmacological Class

    SNRI.

    See Also

    How Supplied

    XR caps—15, 30, 90; Tabs—Contact supplier

    How Supplied

    Effexor XR is supplied in 15-, 30-, and 90-count bottles, and a carton of 10 Redipak blister strips of 10 capsules each. Effexor XR is available in the following strengths:

    • 37.5 mg – grey cap/peach body with “W” and “Effexor XR” on the cap and “37.5” on the body

    • 75 mg –  peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body

    • 150 mg –  dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body

     

    Storage

    Store at controlled room temperature, 20° to 25°C (68° to 77°F). 

    Manufacturer

    Various generic manufacturers

    Generic Availability

    YES

    Mechanism of Action

    Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

    Venlafaxine Indications

    Indications

    Major depressive disorder (MDD).

    Venlafaxine Dosage and Administration

    Prior to Treatment Evaluations

    Screen for personal or family history of bipolar disorder, mania, or hypomania.

    Adult

    Take with food. ≥18yrs: Initially 75mg/day in 2–3 divided doses; may increase at 4-day intervals in 75mg/day increments to 150mg/day; max 375mg/day, in 3 divided doses. Hepatic impairment: reduce by at least 50%. Renal impairment (mild or moderate): reduce by 25–50%; (severe or undergoing hemodialysis): reduce dose by at least 50%. Withdraw gradually (over 2 weeks).

    Children

    <18yrs: not established.

    Renal impairment

    Mild (CrCl 60-89 mL/min) or moderate (CrCl 30-59 mL/min) renal impairment: reduce the Effexor XR total daily dose by 25% to 50%.

    Severe renal impairment (CrCl <30 mL/min) or patients undergoing hemodialysis: reduce the Effexor XR total daily dose by 50% or more.

    Hepatic Impairment

    Mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment: reduce the Effexor XR total daily dose by 50%.

    Severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis: reduce the Effexor XR total daily dose by 50% or more.

    Nursing Considerations

    Alert patients and caregivers to monitor for the emergence of unusual behaviors, worsening depression, or suicidal ideation.

    Venlafaxine Contraindications

    Contraindications

    During or within 14 days of MAOIs (see Interactions). Concomitant linezolid or IV methylene blue.

    Venlafaxine Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Boxed Warning

    Suicidal Thoughts and Behaviors 

    • Increased risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies.

    • Monitor closely for clinical worsening, and emergence of suicidal thoughts and behaviors.

    • Not approved for use in pediatric patients.

    Venlafaxine Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thinking and behavior in children, adolescents, and young adults; monitor closely for clinical worsening or unusual changes. Screen for bipolar disorder, mania or hypomania prior to initiation. Monitor for serotonin syndrome; discontinue immediately if occurs. Pre-existing hypertension, cardio- or cerebrovascular disease. Monitor BP before and during treatment; consider dose reduction or discontinuation if elevated BP persists. Heart disease (eg, recent MI, heart failure). Risk for bleeding events. Angle-closure glaucoma. Avoid in those with untreated anatomically narrow angles. History of mania/hypomania. Seizure disorders. Volume-depleted. Hyponatremia (esp. in elderly). Sexual dysfunction. Renal or hepatic dysfunction. Avoid abrupt disruption; monitor. Reevaluate periodically. Write ℞ for smallest practical amount. Elderly. Labor & delivery. Pregnancy; see full labeling for effects on mother and neonates. Nursing mothers.

    Warnings/Precautions

    Suicidal Thoughts and Behaviors in Adolescents and Young Adults

    • The risk of suicidal thoughts and behaviors in children, adolescents, and young adults is unknown with long-term use (eg, beyond 4 months).

    • Monitor all patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months and at times of dosage changes.

    • Counsel caregivers or family members to monitor for changes in behavior and to alert the healthcare provider.

    • If depression is persistently worse or who are experiencing emergent suicidal thoughts or behaviors, consider changing the therapeutic regimen, including discontinuing treatment.

    Serotonin Syndrome

    • See Interactions.

    • Risk of life-threatening serotonin syndrome: increased risk when Effexor XR is used concomitantly with other serotonergic drugs (including triptans, TCAs, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and drugs that impair metabolism of serotonin (eg, MAOIs).

    • Do not initiate in patients who are being treated with MAOIs (eg, linezolid or IV methylene blue). If concomitant use is necessary with an MAOI, discontinue Effexor XR before initiation of MAOI.

    • Monitor for emergence of serotonin syndrome.

    • Discontinue immediately if serotonin syndrome occurs and initiate supportive symptomatic treatment.

    Elevated Blood Pressure

    • Monitor blood pressure prior to initiation and regularly during treatment. Control pre-existing hypertension prior to initiation.

    • Use caution in patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions.

    • Consider reducing dose or discontinuing treatment if sustained increase in blood pressure occurs.

    Increased Risk of Bleeding  

    • See Interactions.

    • Concomitant use with aspirin, NSAIDs, warfarin, other anticoagulants or other drugs known to affect platelet function may increase the risk of bleeding.

    • Advise patients about the increased risk of bleeding when Effexor XR is coadministered with NSAIDs, aspirin, or other drugs. 

    • If Effexor XR is used with warfarin, monitor coagulation indices when initiating, titrating, or discontinuing Effexor XR.

    Angle-Closure Glaucoma 

    • Effexor XR may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

    • Avoid use in patients with untreated anatomically narrow angles.

    Activation of Mania or Hypomania

    • Treatment with Effexor XR may precipitate a mixed/manic episode.

    • Screen for any personal or family history of bipolar disorders, mania, or hypomania prior to initiating treatment with Effexor XR.

    Discontinuation Syndrome

    • Monitor for discontinuation symptoms when discontinuing treatment with Effexor XR.

    • A gradual dosage reduction is recommended. Do not abruptly discontinue Effexor XR.

    Seizures

    • Use caution in patients with a seizure disorder.

    Hyponatremia

    • Greater risk of developing hyponatrema with SNRIs in elderly patients, patients taking diuretics, or those who are otherwise volume-depleted.

    • Consider discontinuing treatment with Effexor XR in patients with symptomatic hyponatremia, and institute appropriate medical intervention.

    Weight and Height Changes in Pediatric Patients  

    • Effexor XR is not approved for use in pediatric patients.

    Interstitial Lung Disease and Eosinophilic Pneumonia 

    • Rare reports of interstitial lung disease and eosinophilic pneumonia.

    • If this occurs, patients should undergo a prompt medical evaluation and consider discontinuing Effexor XR.

    Sexual Dysfunction

    • SNRIs, including Effexor XR, may cause symptoms of sexual dysfunction.

    • Prescribers should inquire about sexual function prior to initiation and about changes in sexual function during treatment.

    Pregnancy Considerations

    Pregnancy Exposure Registry 

    Risk Summary 

    • Available data from published epidemiologic studies on use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes.

    • Available data from observational studies with venlafaxine have identified a potential increased risk for preeclampsia when used during mid to late pregnancy; exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage.

    Clinical Considerations

    • Disease-Associated Maternal and/or Embryo/Fetal Risk: Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

    • Maternal Adverse Reactions: Use in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk of postpartum hemorrhage.

    • Fetal/Neonatal Adverse Reactions: Neonates exposed to SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Monitor neonates exposed to Effexor XR in the third trimester of pregnancy for drug discontinuation syndrome.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Effexor XR and any potential adverse effects on the breastfed child or from the underlying maternal condition.

    Pediatric Considerations

    Safety and efficacy have not been established.

    Geriatric Considerations

    No overall differences in efficacy or safety were observed between elderly patients and younger patients.

    Greater sensitivity of some older individuals cannot be ruled out.

    Cases of clinically significant hyponatremia have been associated with elderly patients who may be at greater risk for this adverse event.

    Renal Impairment Considerations

    Dosage adjustment is recommended in patients with mild (CrCl = 60–89 mL/min), moderate (CrCl = 30–59 mL/min), or severe (CrCl <30 mL/min) renal impairment, and in patients undergoing hemodialysis.

    Hepatic Impairment Considerations

    Dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment or hepatic cirrhosis.

    Venlafaxine Pharmacokinetics

    Absorption

    Venlafaxine is well absorbed. At least 92% of a single oral dose of venlafaxine is absorbed.

    Absolute bioavailability is ~45%.

    Distribution

    Venlafaxine is 27% and O-desmethylvenlafaxine (ODV) is 30% bound to plasma proteins. Apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV.

    Metabolism

    Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to O-desmethylvenlafaxine (ODV), but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. 

    Elimination

    Renal (87%). Half-life: 5±2 hours (for venlafaxine); and 11±2 hours (for O-desmethylvenlafaxine). Mean ± SD plasma apparent clearance at steady-state: 1.3±0.6 L/h/kg (for venlafaxine); and 0.4±0.2 L/h/kg (for O-desmethylvenlafaxine). 

     

    Venlafaxine Interactions

    Interactions

    See Contraindications. Allow at least 14 days after MAOI discontinuance before starting venlafaxine; allow at least 7 days after venlafaxine discontinuance before starting an MAOI. Increased risk of serotonin syndrome with concomitant other serotonergic drugs (eg, other SNRIs, SSRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, methadone, meperidine, tryptophan, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs such as linezolid, IV methylene blue). Avoid alcohol. Potentiated by CYP3A inhibitors; consider reducing dose of venlafaxine. Potentiates CYP2D6 substrates; consider reducing dose of substrate. Concomitant weight loss agents (eg, phentermine), serotonin precursors (tryptophan supplements): not recommended. Caution with other CNS drugs, cimetidine, haloperidol, diuretics, metoprolol, drugs that inhibit CYP2D6, CYP3A4. Increased risk of bleeding with aspirin, NSAIDs, warfarin, or other drugs that affect coagulation; monitor closely. False (+) urine immunoassay screening tests for PCP and amphetamine.

    Venlafaxine Adverse Reactions

    Adverse Reactions

    Nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, decreased libido, weight changes, dizziness, insomnia, headache, nervousness, asthenia, vasodilation, abnormal dreams or vision, tremor, yawn, ecchymosis; rare: interstitial lung disease, eosinophilic pneumonia.

    Venlafaxine Clinical Trials

    Clinical Trials

    Major Depressive Disorder (MDD)

    Study 1 and 2

    • The efficacy of Effexor XR was based on 2 placebo-controlled, short-term (8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients diagnosed with MDD. 

    • Moderately depressed patients were initiated with venlafaxine 75 mg/day.

    • Both studies showed that treatment with Effexor XR achieved superiority over placebo on the primary efficacy outcome, defined as change from baseline in the HAM-D-21 total score to the endpoint visit, and on the key secondary efficacy outcome, the Clinical Global Impressions (CGI) Severity of Illness scale.

    Study 3

    • The efficacy of Effexor XR was based on a 4-week study of inpatients diagnosed with MDD with melancholia, with doses of Effexor in a range of 150 to 375 mg/day (divided 3 times daily).

    • Treatment with Effexor achieved superiority over placebo based on the HAM-D-21 total score.

    Study 4

    • In the longer-term 26-week Study 4, adult outpatients with MDD who responded to an 8-week open-label study on Effexor XR (75, 150, or 225 mg once daily) were randomly assigned to continuation of their same Effexor XR dose or placebo.

    • Response during the open-label phase was defined as CGI Severity of Illness item score of at least 3 and a HAM-D-21 total score of less than or equal to 10 at the day 56 evaluation.

    • Relapse during the double-blind phase was defined as: (1) a reappearance of MDD as defined by DSM-IV criteria and a CGI Severity of Illness item score of at least 4 (moderately ill), (2) two consecutive CGI Severity of Illness item scores of at least 4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. 

    • Treatment with Effexor XR achieved statistically significantly lower relapse rates over 26 weeks vs placebo.

    Study 5

    • In the second longer-term 52-week Study 5, adult outpatients with MDD, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved were randomly assigned to continue the same Effexor dose or to placebo.

    • Treatment with Effexor XR achieved statistically significantly lower relapse rates over 56 weeks vs placebo.

    Venlafaxine Note

    Not Applicable

    Venlafaxine Patient Counseling

    Patient Counseling

    Suicidal Thoughts and Behaviors

    • Advise to look for the emergence of suicidal ideation and behavior, especially early during treatment and dose adjustments. Report symptoms to healthcare provider.

    Concomitant Medication

    • Do not take Effexor with MAOI or within 14 days of stopping an MAOI.

    Serotonin Syndrome

    • Caution about the risk of serotonin syndrome. Report to emergency room if signs or symptoms of serotonin syndrome occur.

    Elevated Blood Pressure

    • Monitor blood pressure regularly while taking Effexor XR.

    Increased Risk of Bleeding

    • Use of Effexor XR with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    • Inform your healthcare provider of any prescription or OTC medications you are currently taking or plan to take.

    Activation of Mania/Hypomania

    • Look for signs of activation.

    Cardiovascular/Cerebrovascular Disease

    • Use caution in patients with cardiovascular, cerebrovascular, or lipid metabolism disorders.

    Serum Cholesterol and Triglyceride Elevation

    • Elevations in total cholesterol, LDL and triglycerides may occur and consider measuring serum lipids.

    Discontinuation Syndrome

    • Do not abruptly stop taking Effexor XR. Monitor for discontinuation symptoms.

    Sexual Dysfunction

    • May cause sexual dysfunction in male and female patients. Discuss any changes and potential management strategies with your healthcare provider.

    Interference with Cognitive and Motor Performance 

    • Use caution when operating hazardous machinery, including automobiles.

    Alcohol

    • Avoid alcohol during treatment.

    Allergic Reactions

    • Notify healthcare provider if allergic phenomena such as rash, hives, swelling, or difficulty breathing, develops.

    Pregnancy

    • Advise pregnant women that Effexor XR use during mid to late pregnancy may lead to an increased risk for preeclampsia. Use in late pregnancy may lead to an increased risk for postpartum hemorhage and may increase the risk for neonatal complications. 

    Residual Spheroids  

    • Effexor XR contains spheroids, which release the drug slowly into the digestive tract. 

    • Patients may notice spheroids passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the spheroids. 

    Cost Savings Program

    Effexor XR Savings Card

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