Venlafaxine, a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI), is a phenylethylamine-derivative antidepressant and anxiolytic agent.1, 3, 54, 55
Venlafaxine is commercially available in the US as venlafaxine hydrochloride and as venlafaxine besylate.1, 3, 54, 55
Venlafaxine hydrochloride conventional tablets are used in adults for the treatment of major depressive disorder.1 Venlafaxine hydrochloride extended-release capsules are used in adults for the treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder.3 Venlafaxine hydrochloride extended-release tablets are used in adults for the treatment of major depressive disorder and social anxiety disorder.54
Venlafaxine besylate extended-release tablets are used in adults for the treatment of major depressive disorder and generalized anxiety disorder.55
Venlafaxine hydrochloride and venlafaxine besylate are used in the treatment of major depressive disorder in adults.1, 3, 54, 55 The manufacturers state that venlafaxine hydrochloride and venlafaxine besylate products are not approved for use in pediatric patients.1, 3, 54, 55
Efficacy of venlafaxine conventional tablets for the management of major depressive disorder has been established in several placebo-controlled studies in outpatient settings in patients who had major depressive disorder and in 1 placebo-controlled study in a hospital setting in patients who had major depressive disorder with melancholia.1, 8, 56, 57, 58, 59 Efficacy of venlafaxine hydrochloride extended-release capsules and tablets and venlafaxine besylate extended-release tablets for the treatment of major depressive disorder also have been established by several placebo-controlled studies.3, 6, 54, 55, 60
In 4 studies of 6 weeks' duration in adult outpatients with major depressive disorder, venlafaxine in dosages of 75-225 mg daily administered in 2 or 3 divided doses as conventional tablets was found to be superior to placebo on at least 2 of the following 3 clinical measures of depression: Hamilton Depression Rating Scale (HAM-D) total score, HAM-D depressed mood item, and the Clinical Global Impression (CGI) Severity of Illness Scale.1 In these studies, higher dosages (i.e., dosages exceeding 225 mg daily) were not associated with greater response.1, 3 In 2 short-term (8 or 12 weeks), placebo-controlled, flexible-dose (75-225 mg daily) studies with venlafaxine extended-release capsules in adult outpatients, venlafaxine was found to be superior to placebo on the same clinical measures of depression that were used in the studies of venlafaxine conventional tablets, as well as on the Montgomery-Asberg Depression Rating Scale (MADRS) total score and certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, the retardation factor, and the psychic anxiety score.3, 6
Venlafaxine hydrochloride conventional tablets also have been shown to be superior to placebo in the management of major depressive disorder with melancholia in a hospital setting.1, 3, 8, 54 In a study of 4 weeks' duration, 65% of hospitalized patients with major depressive disorder and melancholia who received venlafaxine 150-375 mg daily (mean dosage of 350 mg daily) administered in 3 divided doses as conventional tablets had at least a 50% reduction in MADRS total score compared with 28% of those who received placebo.1, 3, 8 Patients who participated in this study had a mean baseline MADRS total score of 35 (range: 26-48); those with a baseline score of 4 or greater on the suicidal thought item of the MADRS were excluded from the study.8
Results of long-term, relapse prevention studies in outpatients with major depressive disorder indicate that venlafaxine's antidepressant effects are maintained for up to 1 year.1, 3, 58, 60 In one study, patients who responded to an initial 26-week course of venlafaxine 100-200 mg daily in 2 divided doses (as hydrochloride conventional tablets) were randomized to receive either venlafaxine (same dosage range) or placebo.1, 3, 54, 58 In another study, patients who responded to an initial 8-week course of venlafaxine 75-225 mg once daily (as hydrochloride extended-release capsules) were randomized to receive either venlafaxine (same dosage range) or placebo.1, 4, 54, 55, 60 Patients receiving venlafaxine in both studies experienced substantially lower relapse rates than those receiving placebo.1, 4, 54, 55, 58, 60 Relapse was defined in clinical studies with venlafaxine conventional tablets as a score of 4 or greater on the CGI Severity of Illness Scale and in clinical studies with venlafaxine extended-release capsules as a reappearance of major depressive disorder as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria and a CGI Severity of Illness Scale score of 4 or greater (i.e., moderately severe depression), 2 consecutive scores of 4 or greater on the CGI Severity of Illness Scale, or a final CGI Severity of Illness Scale score of 4 or greater for any patient who withdrew from the study for any reason.1, 3, 54, 55, 58, 60
Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.61, 62, 63, 64 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.61, 62, 63, 64 In general, these drugs have shown similar effectiveness; therefore, treatment is guided by specific patient- and drug-related factors.61, 62, 63, 64
A legacy practice guideline from the American Psychiatric Association (APA) states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of these 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).61 Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost.61
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder.62 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.62 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, an SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.62 No evidence is available to suggest superiority of one agent over another.62 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.62 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.62
Venlafaxine hydrochloride extended-release capsules (i.e., Effexor XR®) and venlafaxine besylate extended-release tablets are used in the treatment of generalized anxiety disorder in adults.3, 55 The manufacturers state that venlafaxine hydrochloride extended-release capsules (Effexor XR®) and venlafaxine besylate extended-release tablets are not approved for use in pediatric patients.3, 55
Venlafaxine has also been used for the treatment of generalized anxiety disorder in pediatric patients ≥6 years of age† .65
Efficacy of venlafaxine extended-release capsules for the management of generalized anxiety disorder in adults has been established in 4 randomized, multicenter, placebo-controlled studies of 2 or 6 months' duration in adult outpatients with generalized anxiety disorder.3, 4, 7, 9, 55 Three studies employed fixed venlafaxine dosages, and the other employed a flexible dosing schedule.3, 4, 7, 9, 55 In the flexible-dose study, approximately 69% of patients receiving venlafaxine 75-225 mg daily (as extended-release capsules) were categorized as responders (defined as a 40% or greater reduction from baseline in the Hamilton Rating Scale for Anxiety [HAM-A] total score or a score of 1 [“very much improved”] or 2 [“much improved”] on the CGI Global Improvement Scale) during weeks 6-28 of therapy compared with 42-46% of those receiving placebo.4 In separate clinical studies of 2 or 6 months' duration employing fixed dosages of venlafaxine of 37.5, 75, 150, or 225 mg daily (as extended-release capsules), venlafaxine was shown to be substantially more effective than placebo on HAM-A total score, both the HAM-A anxiety and tension items, and the CGI Scale.3, 7, 9, 55 While a relationship between dosage (over the dosage range of 75-225 mg daily) and efficacy in generalized anxiety disorder has not been definitively established,3, 7, 55 dosages of 37.5 mg daily were not as consistently effective in one study as dosages of 75 or 150 mg daily.3, 9, 55
Guidelines from international experts state that the SSRIs escitalopram, paroxetine, and sertraline, as well as the SNRIs venlafaxine and duloxetine, are first-line pharmacologic treatments for generalized anxiety disorder in adults.66
The American Academy of Child and Adolescent Psychiatry (AACAP) guideline for anxiety disorders provides recommendations for pediatric patients with generalized anxiety disorder.65 Cognitive-behavioral therapy is recommended for patients 6-18 years of age with generalized anxiety disorder.65 AACAP recommends that an SSRI be offered to patients in this age group if pharmacotherapy is needed.65 An SNRI, such as duloxetine or venlafaxine, could also be offered.65 Choice of therapy should be based on pharmacokinetics, pharmacodynamics, tolerability, cost, unique risks, warnings or precautions, and insurance formularies.65 Guidelines from international experts state that fluvoxamine, fluoxetine, sertraline, duloxetine, and venlafaxine are effective in treating generalized anxiety disorders and mixed anxiety disorders in children and adolescents.66
Venlafaxine hydrochloride extended-release capsules (i.e., Effexor XR®) and venlafaxine hydrochloride extended-release tablets are used in the treatment of social anxiety disorder in adults.3, 54 The manufacturer states that venlafaxine hydrochloride extended-release capsules (Effexor XR®) and venlafaxine besylate extended-release tablets are not approved for use in pediatric patients.3, 54
Venlafaxine has also been used for the treatment of social anxiety disorder in pediatric patients ≥6 years of age†.65
Efficacy of venlafaxine extended-release capsules in the treatment of social anxiety disorder has been established in several multicenter, placebo-controlled studies of 12 weeks' duration and a placebo-controlled study of 6 months' duration in adult outpatients with social anxiety disorder.3, 54, 67, 68, 69, 70, 71 In these studies, venlafaxine 75-225 mg daily (as extended-release capsules) was substantially more effective than placebo, as determined by change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score.3, 54, 67, 68, 69, 70, 71 In 2 of the 12-week studies, venlafaxine was also compared to paroxetine (20-50 mg/day); no substantial differences were noted between extended-release venlafaxine and paroxetine.67, 69 In the 6-month study, there was no evidence for better efficacy of venlafaxine at dosages of 150-220 mg daily versus 75 mg daily.3, 71
Subgroup analysis of these controlled studies in adult outpatients with social anxiety disorder did not reveal any evidence of gender-related differences in treatment outcome; there was insufficient information to determine the effect of age or race on outcome in these studies.3, 54
Guidelines from international experts state that escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine are recommended first-line agents for the pharmacological treatment of social anxiety disorder in adults.66
The AACAP guideline for the assessment and treatment of children and adolescents with anxiety disorders provides recommendations for pediatric patients with social anxiety disorder.65 Cognitive-behavioral therapy is recommended for patients 6 to 18 years of age.65 AACAP also recommends that an SSRI be offered to patients in this age group.65 An SNRI, such as duloxetine or venlafaxine, could also be offered.65 Choice of medication for anxiety in children and adolescents should be based on pharmacokinetics, pharmacodynamics, tolerability, cost, unique risks, warnings, or precautions, and insurance formularies.65 Guidelines from international experts state that venlafaxine and paroxetine have been found to be effective in children and adolescents with social anxiety disorder based on a single placebo-controlled study for each agent.66
Venlafaxine hydrochloride extended-release capsules (i.e., Effexor XR®) are used in the treatment of panic disorder in adults.3 The manufacturer states that venlafaxine extended-release capsules (Effexor XR®) are not approved for use in pediatric patients.3
Venlafaxine has also been used for the treatment of panic disorder in pediatric patients ≥6 years of age† .65
Efficacy of venlafaxine extended-release capsules in the treatment of panic disorder has mainly been established in 2 multicenter, double-blind, placebo-controlled studies of 12 weeks' duration in adult outpatients with panic disorder with or without agoraphobia.3, 39, 40 Venlafaxine was given in a fixed dosage of 75 or 150 mg once daily (as extended-release capsules) in one study and in a fixed dosage of 75 or 225 mg once daily (as extended-release capsules) in the other study.3, 39, 40 Venlafaxine was found to be substantially more effective than placebo, as determined by percentage of patients free of full-symptom attacks on the Panic and Anticipatory Anxiety Scale (PAAS), mean change from baseline on the Panic Disorder Severity Scale (PDSS) total score, and the percentage of patients rated as responders on the CGI Improvement Scale.3, 39, 40 While a relationship between dosage (over the dosage range of 75-225 mg daily) and efficacy in panic disorder has not been definitively established, efficacy was established for each dosage studied in these 2 trials.3, 39, 40
Subgroup analysis of these controlled studies in adult outpatients with panic disorder did not reveal any evidence of gender-related differences in treatment outcome; there was insufficient information to determine the effect of age or race on outcome in these studies.3
In a longer-term study, patients with panic disorder who had responded during the 12-week open phase of a clinical trial with venlafaxine 75, 150, or 225 mg once daily (as extended-release capsules) were randomly assigned to either continue receiving venlafaxine in the same dosage range or be switched to placebo and observed for relapse.3, 72 Relapse was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued therapy due to loss of effectiveness as determined by the study investigators.3, 72 Patients who continued receiving venlafaxine therapy experienced a significantly longer time to relapse than those receiving placebo in this study.3, 72
Legacy guidelines from the APA state that SSRIs, SNRIs, TCAs, benzodiazepines, and cognitive behavioral therapy have all demonstrated efficacy for the initial treatment of panic disorder.73 Evidence is insufficient to recommend any of these pharmacological or psychosocial interventions over others; choice of initial therapy should be based on patient preference, past treatment history, the presence of comorbid medical or psychiatric conditions, potential adverse effects, potential drug interactions, cost, and treatment availability.73 For patients who prefer to initiate pharmacological treatment, SSRIs and SNRIs are typically recommended first line.73 TCAs and benzodiazepines have similar efficacy to SSRIs and SNRIs, but are less favorable as initial therapy due to their side effect profiles and warnings for use.73 Updated guidelines from international experts state that first-line medications for the treatment of panic disorder include citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, and venlafaxine.66
The AACAP guideline for the assessment and treatment of children and adolescents with anxiety disorders provides recommendations for pediatric patients with panic disorder.65 Cognitive-behavioral therapy is recommended for patients 6 to 18 years of age with panic disorder.65 AACAP also recommends that an SSRI be offered to patients in this age group.65 An SNRI, such as duloxetine or venlafaxine, could also be offered.65 Choice of medication for panic disorder in children and adolescents may depend on pharmacokinetics, pharmacodynamics, tolerability, cost, unique risks, warnings, or precautions, and insurance formularies.65
Venlafaxine has been used for the management of vasomotor symptoms (VMS)† in women with breast cancer20, 21, 22, 23 , in postmenopausal women,24, 25, 74, 75, 76 and in men with cancer.80, 81
In a randomized, double-blind, placebo-controlled study in 191 women with breast cancer (69% were receiving tamoxifen) who were experiencing 2 or more episodes of hot flushes daily, the percentage reductions in hot flush severity score at 4 weeks of treatment were 27% for placebo, 37% for venlafaxine 37.5 mg daily, 61% for venlafaxine 75 mg daily, and 61% for venlafaxine 150 mg daily.20 Comparisons among treatment groups showed that all 3 venlafaxine dosages were associated with a substantial reduction in hot flush frequency and severity; in addition, the 75-mg dosage was more effective than the 37.5-mg dosage, but the 150-mg dosage provided no additional benefit.20
In a randomized, double-blind, placebo-controlled study in 80 postmenopausal women who were experiencing more than 14 hot flushes weekly, 12 weeks of venlafaxine 75 mg daily was associated with a 51% reduction in hot flush score (patient's perception of hot flush interference with daily living).24 Although there was a reduction in hot flush severity, the difference was not substantial.24
Guidelines for interventions to address sexual problems in people with cancer have been published by the American Society of Clinical Oncology (ASCO).80 Included within the ASCO guidelines are recommendations for men and women with VMS.80 For women, hormone therapy is the most effective intervention; however, systemic hormone therapy is contraindicated in patients with hormone-sensitive breast cancer.80 If unable to or unwilling to use hormonal therapy, alternatives for women listed by ASCO include paroxetine, venlafaxine, gabapentin, or clonidine.80 For men with cancer and VMS, ASCO states that medication should be offered for symptomatic improvements; options include venlafaxine, medroxyprogesterone acetate, cyproterone acetate, and gabapentin.80 For men with prostate cancer receiving androgen-deprivation therapy (ADT), SSRIs, SNRIs, or gabapentin may offer symptom relief; however, ASCO states that further clinical investigation is required to validate this recommendation.81 Clinicians should discuss the risks, benefits, and costs of available therapies for possible symptom relief in patients with VMS with ADT.81
Recommendations for the management of menopausal symptoms have been published by the American College of Obstetricians and Gynecologists (ACOG), the Endocrine Society, and the North American Menopause Society (NAMS).74, 75, 76 In general, systemic hormone therapy with estrogen alone or estrogen in combination with progestin is considered the most effective therapy for VMS related to menopause.74, 75, 76 For women who either cannot or choose not to take systemic hormone therapy, effective non-hormonal alternatives for VMS associated with menopause may include SSRIs, SNRIs (including venlafaxine), gabapentin, and fezolinetant.74, 75, 76
Venlafaxine has been used for the management of posttraumatic stress disorder (PTSD)† in adults.77, 78, 79
A Cochrane review of pharmacological treatments for PTSD assessed the effects of several classes of medications, including alpha-blockers, anticonvulsants, antihistamines, SSRIs, and SNRIs, for reducing PTSD symptoms in adults.77 No studies were identified that investigated the number of participants who responded to venlafaxine versus placebo; however, benefit was found in reducing total PTSD symptoms on the Clinician Administered PTSD Scale (CAPS), CGI Severity score, and Davidson Trauma Scale (DTS).77
The Department of Veterans Affairs and Department of Defense have developed guidelines for the treatment of PTSD.78 These guidelines recommend specific types of psychotherapy (e.g., cognitive processing therapy, eye movement desensitization and reprocessing, prolonged exposure therapy) over pharmacologic interventions for PTSD.78 If pharmacologic therapy is used, the guidelines recommend paroxetine, sertraline, or venlafaxine; there is insufficient evidence to recommend for or against other medications (including other SSRIs) for the treatment of this condition.78 Guidelines from international experts state that first-line medications for the treatment of PTSD include SSRIs (fluoxetine, paroxetine, sertraline) and venlafaxine.79
Venlafaxine has been used for the management of affective premenstrual symptoms in premenstrual disorders †82 , neuropathic pain in patients with diabetes†, 83 obsessive-compulsive disorder (OCD) in adults†, 79, 84 and prevention of migraines in adults†.86, 87
Guidelines from ACOG provide recommendations for the management of premenstrual disorders.82 For the management of affective premenstrual symptoms, ACOG recommends SSRIs as first-line; there is limited evidence that shows venlafaxine also improves premenstrual symptoms.82
The American Diabetes Association (ADA) guidelines for retinopathy, neuropathy, and foot care recommend gabapentinoids, SNRIs (e.g. duloxetine, venlafaxine, desvenlafaxine), TCAs, and sodium channel blockers as initial pharmacologic treatments for neuropathic pain in patients with diabetes.83
Legacy guidelines from APA for OCD list SSRIs as first-line pharmacotherapy.84 Patients who do not respond to an SSRI can switch to another SSRI; there is also evidence to support switching to venlafaxine, mirtazapine, or clomipramine, or augmenting with a second-generation antipsychotic.84 International experts provide a limited recommendation for the use of venlafaxine in OCD.79
Guidelines from the American Academy of Neurology (AAN) and American Headache Society (AHS) list several medications as effective, probably effective, and possibly effective for migraine prevention.85 Among several other medications (including amitriptyline, atenolol, and naratriptan), venlafaxine is listed as probably effective and should be considered for migraine prevention.85 An updated position statement from the AHS added calcitonin gene-related peptide (CGRP) inhibitors as first-line therapies for the prevention of episodic or chronic migraine without a requirement for the prior failure of other classes of migraine preventive treatment (i.e., antidepressants).86 The Department of Veterans Affairs and Department of Defense have developed guidelines for headache and state there is insufficient evidence to recommend for or against venlafaxine for the prevention of headache.87
Dispensing and Administration Precautions
Venlafaxine hydrochloride and venlafaxine besylate are administered orally.1, 3, 54, 55
Venlafaxine hydrochloride conventional tablets are administered in divided doses 2 or 3 times a day with food.1 Venlafaxine hydrochloride extended-release capsules and tablets and venlafaxine besylate extended-release tablets are administered once daily, either in the morning or in the evening at approximately the same time each day, with food.3, 54, 55 Food does not appear to affect GI absorption of venlafaxine hydrochloride.1, 3, 54 Ingestion of a high-fat meal when taken with venlafaxine besylate extended-release tablets increases plasma concentrations of venlafaxine and its metabolite.55
The extended-release capsules and tablets of venlafaxine hydrochloride and venlafaxine besylate tablets should be swallowed whole with fluid and should not be divided, crushed, chewed, or placed in water.3, 54, 55
The entire contents of venlafaxine hydrochloride extended-release capsules may be sprinkled on a small amount of applesauce immediately prior to administration; the patient should drink some water after swallowing the entire mixture without chewing to ensure that the pellets are completely swallowed.3
Store venlafaxine hydrochloride conventional tablets, venlafaxine hydrochloride extended-release capsules, venlafaxine hydrochloride extended-release tablets, and venlafaxine besylate extended-release tablets at 20-25°C.1, 3, 54, 55 Excursions are permitted between 15-30°C for venlafaxine hydrochloride extended-release tablets and venlafaxine besylate extended-release tablets.54, 55 Protect venlafaxine hydrochloride extended-release tablets from moisture and humidity.54 Keep venlafaxine hydrochloride conventional tablets dry.1
Dosages of venlafaxine hydrochloride and venlafaxine besylate are expressed in terms of venlafaxine.1, 3, 54, 55
For the treatment of major depressive disorder in adults, the recommended initial dosage of venlafaxine is 75 mg daily administered in 2 or 3 divided doses as conventional tablets or as a single daily dose when using the extended-release capsules or tablets.1, 3, 54 According to the manufacturer, an initial dosage of 37.5 mg daily (as extended-release capsules or tablets) for the first 4-7 days (followed by an increase to 75 mg daily) may be considered for some patients.3, 54 If no clinical improvement is apparent, the dosage may be increased by increments of up to 75 mg daily at intervals of not less than 4 days.1, 3, 54 If clinically necessary, dosage can be increased up to 225 mg daily in divided doses as conventional tablets or in a single daily dose when using the extended-release capsules.1, 3, 54 Although studies with venlafaxine conventional tablets in outpatient settings did not demonstrate additional benefit from dosages exceeding 225 mg daily in moderately depressed patients, patients with more severe depression responded to a mean dosage of 350 mg daily.1, 54 Whether higher dosages of venlafaxine extended-release tablets are needed for more severely depressed patients is unknown; however, experience with dosages of venlafaxine extended-release capsule dosages exceeding 225 mg daily is very limited.3 The manufacturer states that venlafaxine dosage should not exceed 375 mg daily (usually administered in 3 divided doses) as conventional tablets or 225 mg daily as extended-release capsules or tablets.1, 3, 54, 55
If desired, patients with depression who are undergoing treatment with a therapeutic dose of conventional tablets may be switched to the extended-release capsules or tablets at the nearest equivalent daily venlafaxine dose (e.g., change 37.5 mg twice daily administered as conventional tablets to a 75-mg extended-release capsule or tablet administered once daily).3, 54, 55
Patients may be initiated on venlafaxine besylate extended-release tablets at a dosage of 112.5 mg once daily for major depressive disorder if they have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days.55
For the management of generalized anxiety disorder in adults, the initial dosage of venlafaxine as extended-release capsules recommended for most patients is 75 mg once daily.3 In some patients, it may be desirable to initiate therapy with a dosage of 37.5 mg daily given for the first 4-7 days, followed by an increase to 75 mg daily.3 Although a dose-response relationship for effectiveness in generalized anxiety disorder was not clearly established in clinical studies, certain patients not responding to a venlafaxine dosage of 75 mg daily may benefit from a higher dosage.3 Dosage in these patients may be increased in increments of up to 75 mg daily at intervals of not less than 4 days up to a maximum dosage of 225 mg daily.3
Patients may be initiated on venlafaxine besylate extended-release tablets at a dosage of 112.5 mg once daily for generalized anxiety disorder if they have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days.55
For the management of social anxiety disorder in adults, the recommended initial dosage of venlafaxine for most patients is 75 mg once daily as extended-release capsules or tablets.3, 54 There is no evidence that higher dosages of venlafaxine confer additional benefit for the treatment of social anxiety disorder.3, 54
For the management of panic disorder in adults, the recommended initial dosage of venlafaxine is 37.5 mg once daily as extended-release capsules for 7 days, followed by 75 mg once daily as extended-release capsules for another 7 days.3 In clinical trials, 37.5 mg once daily was given initially for 7 days, then 75 mg once daily for 7 days; thereafter, dosage was increased in increments of 75 mg once daily every 7 days if necessary up to a maximum dosage of 225 mg daily.3 Dosage in these patients may be increased in increments of up to 75 mg daily at intervals of not less than 7 days up to a maximum dosage of approximately 225 mg daily.3
Although the optimum dosage for the treatment of vasomotor symptoms† in women with breast cancer and in postmenopausal women remains to be established, some clinicians suggest that venlafaxine be initiated at a dosage of 37.5 mg once daily as extended-release capsules, increasing as necessary to 75 mg once daily.20, 34 In one clinical study, 75 mg once daily as extended-release capsules appeared to be optimal.20 Further increases in dosage do not appear to provide substantially increased benefit but are potentially more toxic.20, 21, 24
Although the optimum dosage for the treatment of PTSD in adults† remains to be established, some experts suggest that venlafaxine be initiated at a dosage of 25 mg 2 or 3 times daily as conventional tablets or 37.5 mg once daily as extended-release capsules or tablets.78 Maintenance dosages of venlafaxine for PTSD may range from 75-375 mg in divided doses for conventional tablets and 75-300 mg once daily for extended-release capsules or tablets.78
Decrease the total daily dose of venlafaxine by 50% in patients with mild to moderate hepatic impairment.1, 3, 54, 55 A dosage reduction of >50% and individualization of dosing of venlafaxine may be necessary in patients with severe hepatic impairment or hepatic cirrhosis.1, 3, 54, 55
For venlafaxine besylate extended-release tablets, the maximum dosage recommended in patients with hepatic impairment is 112.5 mg once daily.55 Use another venlafaxine extended-release product if the total daily dosage of venlafaxine is <112.5 mg daily.55
Decrease the total daily dose of venlafaxine by 25—50% in patients with mild to moderate renal impairment.1, 3, 54, 55 Decrease the total daily dose of venlafaxine by 50% or more in patients with severe renal impairment or undergoing hemodialysis.1, 3, 54, 55 Individualization of dosage is recommended in patients due to variability in clearance of venlafaxine in patients with renal impairment.1, 3, 54, 55
For venlafaxine besylate extended-release tablets, the maximum dosage recommended in patients with renal impairment is 112.5 mg once daily.55 Use another venlafaxine extended-release product if the total daily dosage of venlafaxine is <112.5 mg daily.55
No dosage adjustments are recommended for venlafaxine for geriatric patients based on a caution should be exercised.1 Extra care should be taken when increasing and individualizing the dosage.1, 3, 54, 55
Pharmacogenomic Considerations in Dosing
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide dosing recommendations for venlafaxine based on CYP2D6 phenotypes.700 For patients identified as normal CYP2D6 metabolizers, initiate therapy with the recommended starting dosage.700 For patients identified as ultrarapid or intermediate CYP2D6 metabolizers, no action is recommended because of minimal evidence regarding the impact of genotype on efficacy or side effects for venlafaxine.700 For patients identified as poor metabolizers of CYP2D6, consider a clinically appropriate alternative antidepressant not predominately metabolized by CYP2D6.700 No recommendations are given for patients with indeterminate CYP2D6 phenotypes.700
Suicidal Thoughts and Behaviors
A boxed warning on the increased risk of suicidal thoughts and behavior in adolescent and young adult patients taking antidepressants is included in the prescribing information for venlafaxine.1, 3, 54, 55 In pooled analyses of placebo-controlled trials of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other drug classes) that included approximately 77,000 adult patients and 4500 pediatric patients, the incidence of suicidal thoughts and behaviors was greater in patients ≤24 years of age treated with an antidepressant compared to those treated with placebo.1, 3, 54, 55 The incidence of suicidal thoughts and behaviors varied across different antidepressants and indications; however, the risk was increased in young patients for most studied drugs, with the highest incidence in patients with major depressive disorder.1, 3, 54, 55 A reduced risk of suicidal thoughts and behaviors was observed with antidepressants compared with placebo in adults 24-65 years of age and ≥65 years of age.1, 3, 54, 55 Whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use (i.e., >4 months) is unknown.1, 3, 54, 55 However, data from placebo-controlled maintenance trials in adults with major depressive disorder demonstrate that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.1, 3, 54, 55 Monitor all patients treated with antidepressants for any indication of clinical worsening or emergence of suicidal thoughts and behaviors, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1, 3, 54, 55 Counsel families and caregivers to monitor for changes in the patient's behavior, and to report such symptoms to a clinician.1, 3, 54, 55 Consider changing the therapeutic regimen or discontinuing venlafaxine in patients whose depression is persistently worse or in patients experiencing emergent suicidal thoughts or behaviors.1, 3, 54, 55
Other Warnings and Precautions
Serotonergic antidepressants such as venlafaxine can precipitate serotonin syndrome, a potentially life-threatening condition.1, 3, 54, 55 Serotonin syndrome can occur when these medications are used alone, but the risk is increased with concurrent use of other serotonergic drugs (e.g., serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants [TCAs], fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's wort [ Hypericum perforatum ]) and with medications that impair the metabolism of serotonin (i.e., MAOIs).1, 3, 54, 55
Manifestations 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 GI symptoms (e.g., nausea, vomiting, diarrhea).1, 3, 54, 55
Concurrent or recent (i.e., within 14 days) use of MAOIs with venlafaxine is contraindicated.1 Do not initiate venlafaxine in patients treated with MAOIs such as linezolid or IV methylene blue.1, 3, 54, 55 If an MAOI such as linezolid or IV methylene blue is necessary in a patient receiving venlafaxine, discontinue venlafaxine before initiating the MAOI.1, 3, 54, 55
Monitor all patients receiving venlafaxine for the development of serotonin syndrome.1, 3, 54, 55 If manifestations of serotonin syndrome occur, immediately discontinue treatment with venlafaxine and any concurrently administered serotonergic agents, and initiate supportive symptomatic treatment.1, 3, 54, 55
If concurrent therapy with venlafaxine and other serotonergic drugs is clinically warranted, inform patients of the potential increased risk for serotonin syndrome and monitor for symptoms.1, 3, 54, 55
Increases in blood pressure, including sustained elevations, have occurred with venlafaxine treatment in some patients.1, 3, 54, 55
Monitor blood pressure before initiating treatment and during treatment with venlafaxine.1, 3, 54, 55 Use caution in patients with preexisting hypertension, or cardiovascular or cerebrovascular conditions that may be compromised by increases in blood pressure.3, 55 Patients with preexisting hypertension should have blood pressure controlled before initiating treatment with venlafaxine.1, 3, 54, 55 Dosage reduction or drug discontinuation should be considered in patients who experience sustained increases in blood pressure during therapy.1, 3, 54, 55
Sexual dysfunction can occur with the use of serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including venlafaxine; this can include ejaculatory delay or failure, decreased libido, or erectile dysfunction in males, and decreased libido or delayed/absent orgasm in females.1, 3, 54, 55
Providers should inquire about sexual function prior to initiation and during treatment with venlafaxine, since sexual function may not be spontaneously reported.1, 3, 54, 55 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, 3, 54, 55 Potential management strategies should be discussed to support patients in making informed treatment decisions.1, 3, 54, 55
Adverse effects have been reported following discontinuance of venlafaxine, particularly when discontinuation was abrupt.1, 3, 54, 55 These withdrawal effects include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances, somnolence, sweating, tremor, vertigo, vomiting, irritability, lethargy, emotional lability, tinnitus, and seizures.1, 3, 54, 55 Completed suicide, suicidal thoughts, aggression, and violent behavior have also been reported during venlafaxine dosage reduction and discontinuation.3, 55
Gradually reduce dosage (versus abrupt cessation) when discontinuing therapy.1, 3, 54, 55 If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage, then resume more gradual dosage reductions.1, 3, 54, 55 Some patients may require discontinuation of venlafaxine over a period of several months.3, 55
Treatment-emergent anxiety, nervousness, and insomnia have been more commonly reported for patients treated with venlafaxine compared to patients treated with placebo in a pooled analysis of short-term, double-blind, placebo-controlled depression studies, leading to medication discontinuation in some patients.1, 54
Dose-dependent weight loss has been noted in adult patients treated with venlafaxine for several weeks.1, 54
Weight loss has also been noted in pediatric patients receiving venlafaxine hydrochloride extended-release capsules.1, 3, 54, 55 In a pooled analysis of four 8-week clinical trials for major depressive disorder and generalized anxiety disorder, patients treated with venlafaxine hydrochloride extended-release capsules lost an average of 0.45 kg while patients treated with placebo gained an average of 0.77 kg.1, 3, 54, 55 In a longer-term open-label study of children and adolescents who received venlafaxine hydrochloride extended-release capsules for up to 6 months, pediatric patients had weight increases that were less than expected based on data from age- and sex-matched peers.1, 3, 54, 55 The difference between expected weight and observed weight gain was larger for pediatric patients <12 years of age compared to those >12 years of age.1, 3, 54, 55
Height Changes in Pediatric Patients
In 8-week clinical studies in pediatric patients 6 to 17 years of age with generalized anxiety disorder, patients treated with venlafaxine hydrochloride extended-release capsules grew an average of 0.3 cm compared to 1 cm in patients treated with placebo.1, 3, 54, 55 In 8-week clinical trials in pediatric patients with major depressive disorder, patients who received venlafaxine hydrochloride extended-release capsules grew an average of 0.8 cm compared to 0.7 cm in patients treated with placebo.1, 3, 54, 55 In a longer-term open-label study of children and adolescents who received venlafaxine hydrochloride extended-release capsules for up to 6 months, pediatric patients had height increases that were less than expected based on data from age- and sex-matched peers.1, 3, 54, 55 The difference between expected height and observed height gain was larger for pediatric patients <12 years of age compared to those >12 years of age.1, 3, 54, 55
Treatment-emergent anorexia has been more commonly reported for patients treated with venlafaxine compared to patients treated with placebo in a pooled analysis of short-term, double-blind, placebo-controlled depression studies.1, 54
Appetite changes have also been noted in pediatric patients receiving venlafaxine hydrochloride extended-release capsules.1, 3, 54, 55 In 8-week placebo-controlled trials for generalized anxiety disorder and major depressive disorder in pediatric patients 6 to 17 years of age, 10% of patients treated with venlafaxine hydrochloride extended-release capsules reported treatment-emergent anorexia compared to 3% of patients treated with placebo.1, 3, 54, 55
Activation of Mania and Hypomania
Treating a depressive episode with venlafaxine or another antidepressant in patients with bipolar disorder may activate a mixed/manic episode.3, 54, 55 Symptoms of mania or hypomania were reported in 0.5% of patients with venlafaxine hydrochloride conventional tablets.1, 3 Symptoms of mania or hypomania were reported in 0.3% of patients with major depressive disorder, 0% of patients with generalized anxiety disorder, 0.2% of patients with social anxiety disorder, and 0.1% of patients with panic disorder when treated with venlafaxine hydrochloride extended-release capsules.3, 54, 55 Screen patients for any personal or family history of bipolar disorder, mania, or hypomania prior to starting treatment with venlafaxine.3, 54, 55 Use in caution in patients with a history of mania.1
Hyponatremia may occur with use of serotonergic antidepressants, including venlafaxine.1, 3, 54, 55 In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1, 3, 54, 55 Cases with serum sodium concentrations <110 mmol/L have been reported.1, 3, 54, 55 Geriatric individuals, patients receiving diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia.1, 3, 54, 55
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, seizure, coma, respiratory arrest, and death.1, 3, 54, 55
Discontinue venlafaxine in patients with symptomatic hyponatremia, and initiate appropriate medical intervention.1, 3, 54, 55
Seizures have been reported in 0.26% of patients treated with venlafaxine hydrochloride conventional tablets in premarketing studies.1, 3, 54, 55 Venlafaxine has not been systematically evaluated in patients with seizure disorder.3, 55 Use venlafaxine in caution in patients with a history of seizures.1, 3, 54, 55 Discontinue in any patient who develops seizures.1, 3, 54, 55
Selective serotonin-reuptake inhibitors (SSRIs) and SNRIs, including venlafaxine, may increase the risk of bleeding events.1, 3, 54, 55 Concurrent administration of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk.1, 3, 54, 55 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, 3, 54, 55 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. 3, 54, 55
Inform patients about the increased risk of bleeding associated with concomitant use of venlafaxine and antiplatelet agents or anticoagulants.1, 3, 54, 55 For patients taking warfarin, carefully monitor coagulation indices.1, 3, 54, 55
Elevated Serum Cholesterol Concentrations
In clinical studies, clinically relevant increases in serum cholesterol were recorded in patients treated with venlafaxine versus patients treated with placebo.1, 3, 54, 55 Consider monitoring serum cholesterol levels during long-term treatment.1, 3, 54, 55
Interstitial Lung Disease and Eosinophilic Pneumonia
Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine have been reported rarely.1, 3, 54, 55 The possibility of such adverse effects should be considered in patients treated with venlafaxine who present with progressive dyspnea, cough, or chest discomfort.1, 3, 54, 55 Such patients should be evaluated promptly, and discontinuation of venlafaxine should be considered.1, 3, 54, 55
Use in Patients with Concomitant Illness
Venlafaxine has not been systemically evaluated in patients with a recent history of myocardial infarction (MI) or other significant heart disease.1, 54 In clinical trials of venlafaxine, changes in electrocardiogram values and increases in heart rate were observed.1, 54 Use venlafaxine with caution in patients with known diseases that could be exacerbated by increases in heart rate (e.g., hyperthyroidism, heart failure, recent MI).1, 54
Interference with Cognitive and Motor Performance
In clinical studies, no substantial impairment of psychomotor, cognitive, or complex behavior performance was found for patients who received venlafaxine.1, 54 However, since any psychoactive drug may impair judgment, thinking, or motor skills, inform patients about activities that require alertness (e.g., operating heavy machinery and motor vehicles), until they are reasonably certain that venlafaxine does not affect them adversely.1, 3, 54, 55
Antidepressant drugs such as venlafaxine may cause pupillary dilation (mydriasis), which can trigger an angle closure attack in patients without a patent iridectomy with anatomically narrow angles.1, 3, 54, 55
A National Pregnancy Registry for Antidepressants is available that monitors pregnancy outcomes in females exposed to antidepressants during pregnancy.3, 54, 55 Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or by visiting online at [Web].3, 55
Available epidemiologic data with venlafaxine in pregnant females have not established a drug-associated risk of major birth defects, miscarriage, or other adverse developmental outcomes.3, 55
Epidemiologic data found that exposure to SNRIs (including venlafaxine), particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.1, 3, 54, 55
Observational studies have identified a potential increased risk for preeclampsia when venlafaxine is used during mid to late pregnancy.3, 54, 55 There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs during pregnancy.3, 55
In animal reproductive studies, no evidence of malformations or fetotoxicity was observed when venlafaxine was administered during the period of organogenesis at doses up to 2.5 or 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis in rats and rabbits, respectively.1, 3, 54, 55 However, an increase in postnatal mortality and decreased pup weights at 2.5 times the MRHD were observed with administration of venlafaxine to pregnant rats during gestation and lactation.1, 3, 54, 55
Neonates exposed to SNRIs late in the third trimester of pregnancy have developed complications requiring hospitalization, respiratory support, and tube feeding that can arise immediately upon delivery.1, 3, 54, 55 Clinical findings reported to date in neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying.1, 3, 54, 55 These clinical features appear to be consistent with either a direct toxic effect of the SNRI or possibly a drug withdrawal syndrome.1, 3, 54, 55 It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome.1, 3, 54, 55 Neonates exposed to venlafaxine during the third trimester of pregnancy should be monitored for discontinuation syndrome.3, 55 When treating a pregnant female during the third trimester, carefully consider the potential risks and benefits of treatment.1, 54
Venlafaxine and its active metabolite are present in human milk and have not shown adverse reactions in breast-fed infants.1, 3, 54, 55 It is not known if venlafaxine affects milk production.3, 55 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 venlafaxine or the underlying maternal condition.1, 3, 54, 55
The safety and effectiveness of venlafaxine in pediatric patients have not been established; venlafaxine is not approved for use in pediatric patients.1, 3, 54, 55 In 2 placebo-controlled trials in 766 pediatric patients with major depressive disorder and 2 placebo-controlled trials in 793 pediatric patients with generalized anxiety disorder, there were insufficient data to establish the safety and efficacy of venlafaxine for pediatric patients with these conditions.1, 3, 54, 55 Additionally, studies with venlafaxine hydrochloride extended-release capsules suggest that their use in pediatric patients may adversely affect weight and height; decreases in appetite and weight loss have also been observed.1, 3, 54, 55 Studies conducted in pediatric patients 6 to 17 years of age have found that blood pressure and cholesterol increases observed with venlafaxine are clinically relevant and similar to increases seen in adults.1, 3, 54, 55
An increased risk of suicidal thoughts and behaviors was observed in pediatric patients treated with antidepressants.1, 3, 54, 55
In clinical studies with venlafaxine hydrochloride extended-release tablets in major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder, there were 4, 6, 1, and 2% of patients who were ≥65 years of age, respectively.3, 54, 55 In clinical studies with venlafaxine hydrochloride conventional tablets, 12% of patients were ≥65 years of age.1, 3, 54, 55
Overall differences in efficacy and safety have not been observed between geriatric patients and younger patients.1, 3, 54, 55 Geriatric patients may have greater sensitivity to medications and may also be at greater risk of developing hyponatremia.3, 54, 55
Clearance of venlafaxine and its active metabolite is reduced and their half-lives are increased in patients with hepatic cirrhosis and in mild and moderate hepatic impairment.1, 54 In a study with 9 patients with hepatic cirrhosis, the venlafaxine elimination half-life was prolonged by about 30% and its clearance was decreased by about 50% compared to patients with normal hepatic function.1 The half-life of the active metabolite was prolonged by about 60% and its clearance was decreased by about 30%.1, 54 In a study of patients with mild hepatic impairment (Child-Pugh A) and moderate hepatic impairment (Child-Pugh B), oral bioavailability of venlafaxine was increased 2-3 fold, oral elimination half-life was about twice as long and oral clearance was reduced by over half compared to patients with normal hepatic function.1, 54 The oral elimination half-life of the active metabolite of venlafaxine was prolonged by 40% in patients with mild and moderate hepatic impairment and oral clearance was similar to patients with normal hepatic function.1, 54
According to the manufacturer, it is recommended to decrease the total daily dose of venlafaxine by 25-50% in patients with mild to moderate hepatic impairment.1, 3, 54, 55 It is also recommended to decrease the dose by >50% in patients with cirrhosis or severe hepatic impairment; individualization of dosing may be desirable in some patients.1, 3, 54, 55
Clearance of venlafaxine and its active metabolite is reduced in patients with mild to severe renal impairment and in patients on hemodialysis; the half-lives of venlafaxine and its active metabolite are also prolonged.1, 54 Compared to patients with normal renal function, patients with a glomerular filtration rate (GFR) of 10-70 mL/minute were found to have the venlafaxine elimination half-life prolonged by about 50% and clearance of venlafaxine reduced by about 24%.1, 54 The elimination half-life of the active metabolite of venlafaxine was prolonged by 40%; however, clearance of the active metabolite was unchanged in patients with renal impairment compared to patients with normal renal function.1, 54 Compared to patients with normal renal function, patients on dialysis were found to have the venlafaxine elimination half-life prolonged by about 180% and clearance reduced by 57%.1, 54 The elimination half-life of the active metabolite of venlafaxine was prolonged by about 142% and clearance was reduced by about 56% for patients on hemodialysis compared to patients with normal renal function.1, 54
According to the manufacturer, it is recommended to decrease the total daily dose of venlafaxine by 25-50% in patients with mild to moderate renal impairment and by ≥50% in patients with severe renal impairment or undergoing hemodialysis; individualization of dosing may be desirable in some patients.1, 3, 54, 55
Pharmacogenomic Considerations
In patients with the CYP2D6 poor metabolizer phenotype, metabolism of venlafaxine may be decreased.1, 54, 700 In vitro and clinical studies showed that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and decreased levels of its active metabolite.1, 3, 54, 55 Per the manufacturer, the difference between CYP2D6 poor and extensive metabolizers is not expected to be clinically important as venlafaxine and its active metabolite are considered clinically approximate in activity and potency.1, 3, 54, 55 The CPIC guidelines provide dosing recommendations for venlafaxine based on CYP2D6 phenotypes and state that a clinically appropriate alternative antidepressant should be considered for patients who are identified as poor metabolizers of CYP2D6.700
Adverse events reported in ≥5% of patients receiving venlafaxine hydrochloride conventional tablets include asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor and blurred vision, and abnormal ejaculation/orgasm and impotence in men.1
Adverse events reported in ≥5% of patients receiving venlafaxine hydrochloride extended-release capsules (Effexor XR®) include sweating, nausea, anorexia, somnolence, dry mouth, constipation, abnormal ejaculation, impotence in men, and libido decreased.3, 55 The safety of venlafaxine besylate extended-release tablets is based on the extended-release capsules.55
Adverse events reported in ≥5% of patients receiving venlafaxine hydrochloride extended-release tablets for major depressive disorder include sweating, GI complaints (nausea, dry mouth, anorexia), CNS complaints (dizziness, somnolence, abnormal dreams), and abnormal ejaculation.54
Adverse events reported in ≥5% of patients receiving venlafaxine hydrochloride extended-release tablets for social anxiety disorder include asthenia, sweating, GI complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawning, and abnormal vision.54
Venlafaxine is metabolized to its active metabolite O-desmethylvenlafaxine (ODV), principally by cytochrome P-450 (CYP) isoenzyme 2D6.1, 3, 54 Venlafaxine may also be metabolized to a minor metabolite by CYP3A4.1
Venlafaxine is a weak inhibitor of CYP2D6.1, 54
Drugs Affecting Hepatic Microsomal Enzymes
CYP2D6 Inhibitors : Concomitant use of venlafaxine with CYP2D6 inhibitors may reduce the metabolism of venlafaxine.1, 54 However, in a clinical study with CYP2D6 poor and extensive metabolizers, the total concentrations of venlafaxine and its active metabolite were similar in the two metabolizer groups.1, 54 No dosage adjustment is required with concomitant use of venlafaxine and a CYP2D6 inhibitor.1, 54
CYP3A Inhibitors : Concomitant use of venlafaxine with CYP3A inhibitors may increase venlafaxine and ODV plasma concentrations.1, 3, 54, 55 Consider a dosage reduction of venlafaxine with concomitant use of CYP3A inhibitors.1, 3, 54, 55
Drugs Metabolized by Hepatic Microsomal Enzymes
CYP2D6 Substrates : Concomitant use of venlafaxine with CYP2D6 substrates may result in higher peak plasma concentrations and total exposure of the substrate drug, which may lead to an increased risk of toxicity.1, 3, 54, 55 Consider a dosage reduction of the CYP2D6 substrate with concomitant use of venlafaxine.3, 55
The concomitant use of venlafaxine with other CNS-active drugs has not been systematically evaluated; caution is advised when used concomitantly.1, 3
Concomitant use of venlafaxine with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding.1, 3, 55 Monitor for bleeding in patients receiving an antiplatelet or anticoagulant when venlafaxine is initiated or discontinued.1, 3, 55
Venlafaxine is not highly bound to plasma proteins.1, 54 Administration of venlafaxine with another medication that is highly protein bound should not cause increased free concentrations of the other medication.1, 54
Concomitant use of alcohol with venlafaxine had no effect on the pharmacokinetics of venlafaxine or its active metabolite.1, 54 Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, advise patients to avoid alcohol while taking venlafaxine.1, 3, 54, 55
Concomitant use of venlafaxine with cimetidine may increase venlafaxine plasma concentrations.1, 3, 54, 55 When cimetidine was given concomitantly with venlafaxine in healthy subjects, the oral clearance of venlafaxine was reduced by 43% and the AUC and maximum concentration were increased by approximately 60%.1, 54 No dosage adjustment should be necessary for most normal adults; however, caution is advised in patients with preexisting hypertension, elderly patients, and patients with hepatic dysfunction.1, 54
In postmarketing reports, cases of elevated clozapine levels temporally associated with adverse reactions, including seizures, have been reported in patients on clozapine following the addition of venlafaxine.1, 54
In the presence of venlafaxine, desipramine AUC and maximum plasma concentration increased by 35%.1, 54 The AUC of the metabolite of desipramine was also increased by venlafaxine.1, 3, 54
Venlafaxine does not influence the pharmacokinetics of diazepam.1, 3, 54, 55
Concomitant use of venlafaxine with haloperidol may increase haloperidol plasma concentrations.1, 3, 54, 55 In a study of healthy subjects, administration of venlafaxine decreased total oral clearance of a single dose of haloperidol by 42% and increased the haloperidol AUC by 70%.1, 54 The maximum concentration of haloperidol was increased by 88%.1, 54
Venlafaxine does not influence the pharmacokinetics of imipramine.1, 3, 54, 55
Concomitant use of venlafaxine with ketoconazole may increase plasma concentrations of venlafaxine.1, 54 In a pharmacokinetic study, a single dose of venlafaxine was administered with ketoconazole in patients who were poor metabolizers of CYP2D6 and extensive metabolizers of CYP2D6.1, 54 The maximum concentration of venlafaxine and its active metabolite increased by 26% and 14% respectively in extensive metabolizers and by 48% and 29% respectively in poor metabolizers.1, 54
Venlafaxine does not influence the pharmacokinetics of lithium.1, 3, 54, 55
Concomitant use of venlafaxine with metoprolol in healthy male subjects resulted in an increase of plasma concentrations of metoprolol by 30-40%.1, 54 Metoprolol does not influence the pharmacokinetics of venlafaxine or its active metabolite.1, 3, 54, 55
Concomitant use of serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including venlafaxine, with monoamine oxidase inhibitors (MAOIs) increases the risk of serotonin syndrome.1, 3, 54, 55 Concomitant use of venlafaxine with MAOIs, including linezolid or IV methylene blue, is contraindicated.1, 3, 54, 55 Use of venlafaxine within 14 days of stopping an MAOI is contraindicated; in addition, at least 7 days must elapse after stopping venlafaxine before starting an MAOI.1, 3, 54, 55 If an MAOI such as linezolid or IV methylene blue is necessary in a patient receiving venlafaxine, discontinue venlafaxine before initiating the MAOI.1, 3, 54, 55
Concomitant use of venlafaxine with risperidone has been shown to increase the AUC of risperidone by 32%; however, venlafaxine did not alter the pharmacokinetics of the active metabolite of risperidone.1, 54
Concomitant use of venlafaxine and other serotonergic drugs (e.g., selective serotonin-reuptake inhibitors [SSRIs], SNRIs, triptans, tricyclic antidepressants [TCAs], opioids, lithium, buspirone, amphetamines, tryptophan, St. John's Wort) increases the risk of serotonin syndrome.1, 3, 54, 55
Monitor patients for serotonin syndrome, particularly during treatment initiation and with increases in dosage.1, 3, 54, 55 If serotonin syndrome occurs, consider discontinuation of venlafaxine and any concurrently administered serotonergic agents.1, 3, 54, 55
In postmarketing, rare reports of serotonin syndrome have occurred with use of an SSRI and a triptan.1 If concomitant use of venlafaxine with a triptan is clinically warranted, monitor patient closely, especially during treatment initiation and at dosage increases.1
Concomitant use of warfarin with venlafaxine may increase INR; monitor INR during concomitant use.54
The safety and efficacy of venlafaxine in combination with weight loss agents (i.e., phentermine) have not been established; venlafaxine is not indicated for weight loss alone or in combination with other products.1, 3, 55 Concomitant use of venlafaxine and weight loss agents is not recommended.1, 3, 55
Due to lack of specificity in screening tests, false-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients receiving venlafaxine.1, 3, 54, 55 False-positive tests can be expected for several days following the discontinuation of venlafaxine.1, 3, 54, 55 Gas chromatography/mass spectrometry can be used for confirmatory testing to distinguish venlafaxine from PCP and amphetamine.1, 3, 54, 55
Venlafaxine hydrochloride and venlafaxine besylate, selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), are phenylethylamine-derivative antidepressant and anxiolytic agents.1, 3, 54, 55
The exact mechanisms of antidepressant and anxiolytic actions of venlafaxine have not been fully elucidated but appear to be associated with the drug's potentiation of neurotransmitter activity in the CNS.1, 3, 54, 55 Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.1, 3, 54, 55 In vitro studies have demonstrated that venlafaxine and ODV do not possess any significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors.1, 3, 54, 55
Venlafaxine and ODV exhibit linear kinetics over a dosage range of 75-450 mg per day; steady-state concentrations are attained within 3 days.1, 3, 54
The absolute oral bioavailability of venlafaxine is about 45%. 3, 54, 55 The time to achieve peak plasma concentrations of venlafaxine hydrochloride conventional tablets is 2 hours after administration; for venlafaxine hydrochloride extended-release formulations, the time to achieve peak plasma concentrations is 5.5 hours.3, 54 Administration of venlafaxine hydrochloride with food does not affect the rate and extent of absorption of venlafaxine or ODV.1, 3, 54
The time to achieve peak plasma concentrations of venlafaxine besylate extended-release tablets is 5-18 hours.55 Administration of venlafaxine besylate with a high-fat meal increases the mean peak plasma concentration of venlafaxine by 35% and by 22% for ODV.55 The median time to maximum concentration is also altered by food.55
Venlafaxine is about 27% protein bound and ODV is about 30% protein bound.1, 3, 54, 55 The elimination half-life is about 5 hours for venlafaxine hydrochloride and about 11 hours for ODV.1, 3, 54 For venlafaxine besylate extended-release tablets, the elimination half-life is about 6.8 hours for venlafaxine and 11.3 hours for ODV.55 Venlafaxine is extensively metabolized, primarily to ODV, but also to other metabolites including N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine.1, 3, 54, 55 The cytochrome P-450 (CYP) isoenzyme 2D6 is involved in the formation of ODV.1, 3, 54, 55 Venlafaxine is also metabolized via CYP3A, a minor pathway, to N-desmethylvenlafaxine, a minor metabolite.1 Venlafaxine and its metabolites are principally excreted in the urine (87%).1, 3, 54, 55 Pharmacokinetics of venlafaxine are not affected by age or sex.1, 54, 55
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 25 mg (of venlafaxine)* | Venlafaxine Hydrochloride Tablets | |
37.5 mg (of venlafaxine)* | Venlafaxine Hydrochloride Tablets | |||
50 mg (of venlafaxine)* | Venlafaxine Hydrochloride Tablets | |||
75 mg (of venlafaxine)* | Venlafaxine Hydrochloride Tablets | |||
100 mg (of venlafaxine)* | Venlafaxine Hydrochloride Tablets | |||
Tablets, extended-release | 37.5 mg (of venlafaxine)* | Venlafaxine Hydrochloride Extended-release Tablets | ||
75 mg (of venlafaxine)* | Venlafaxine Hydrochloride Extended-release Tablets | |||
150 mg (of venlafaxine)* | Venlafaxine Hydrochloride Extended-release Tablets | |||
225 mg (of venlafaxine)* | Venlafaxine Hydrochloride Extended-release Tablets | |||
Capsules, extended-release | 37.5 mg (of venlafaxine)* | Effexor® XR | Viatris | |
Venlafaxine Hydrochloride Extended-release Capsules | ||||
75 mg (of venlafaxine)* | Effexor® XR | Viatris | ||
Venlafaxine Hydrochloride Extended-release Capsules | ||||
150 mg (of venlafaxine)* | Effexor® XR | Viatris | ||
Venlafaxine Hydrochloride Extended-release Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release | 112.5 mg (of venlafaxine) | Venlafaxine Besylate Extended-release Tablets |
1. Amneal Pharmaceuticals LLC. Venlafaxine hydrochloride tablets prescribing information. Bridgewater, NJ: 2023 Sept.
3. Viatris. Effexor® XR (venlafaxine hydrochloride) extended-release capsules prescribing information. Morgantown, WV: 2023 Aug.
4. Gelenberg AJ, Lydiard RB, Rudolph RL et al. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder. JAMA . 2000; 283:3082-88. [PubMed 10865302]
6. Thase ME for the Venlafaxine XR 209 Study Group. Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. J Clin Psychiatry . 1997; 58:393-8. [PubMed 9378690]
7. Rickels K, Pollack MH, Sheehan DV et al. Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry . 2000; 157:968-74. [PubMed 10831478]
8. Guelfi JD, White C, Hackett D et al. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J Clin Psychiatry . 1995; 56:450-8. [PubMed 7559370]
9. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) in the treatment of generalised anxiety disorder. Br J Psychiatry . 2001; 179:18-22.
20. Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in management of ht flashes in survivors of breast cancer: a randomized controlled trial. Lancet . 2000; 356:2059-63. [PubMed 11145492]
21. Barlow DH. Venlafaxine for hot flushes. Lancet . 2000; 356:2025-6. [PubMed 11145483]
22. van Gool AR, Bannick M, Botenbol M et al. Clinical experience with venlafaxine in the treatment of hot flushes in women witha history of breast cancer. Neth J Med . 2005; 63:175-8. [PubMed 15952486]
23. Stearns V. Managment of hot flashes in breast cancer survivors and men with prostate cancer. Curr Oncol Rep . 2004; 6:285-90. [PubMed 15161582]
24. Evans ML, Pritts E, Vittinghoff E et al. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol . 2005; 105:161-6. [PubMed 15625158]
25. Fugate SE, Church CO. Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. Ann Pharmacother . 2004; 38:1482-99. [PubMed 15292498]
34. The North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of the North American Menopause Society. Menopause. 2004; 11:11-33
39. Bradwejn J, Ahokas A, Stein DJ et al. Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry . 2005; 187:352-9. [PubMed 16199795]
40. Pollack MH, Lepola U, Koponen H et al. A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder. Depress Anxiety . 2006; Aug 7:Epub ahead of print.
54. Zydus Pharmaceuticals (USA) Inc. Venlafaxine hydrochloride extended-release tablets prescribing information. Pennington, NJ; 2023 Sept.
55. Almatica Pharma LLC. Venlafaxine besylate extended-release tablets prescribing information. Morristown, NJ: 2023 Aug.
56. Khan A, Fabre LF, Rudolph R. Venlafaxine in depressed outpatients. Psychopharmacol Bull. 1991;27(2):141-144.
57. Schweizer E, Weise C, Clary C, Fox I, Rickels K. Placebo-controlled trial of venlafaxine for the treatment of major depression. J Clin Psychopharmacol. 1991;11(4):233-236.
58. Entsuah AR, Rudolph RL, Hackett D, Miska S. Efficacy of venlafaxine and placebo during long-term treatment of depression: a pooled analysis of relapse rates. Int Clin Psychopharmacol. 1996;11(2):137-145.
59. Rudolph RL, Fabre LF, Feighner JP, Rickels K, Entsuah R, Derivan AT. A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression. J Clin Psychiatry. 1998;59(3):116-122.
60. Simon JS, Aguiar LM, Kunz NR, Lei D. Extended-release venlafaxine in relapse prevention for patients with major depressive disorder. J Psychiatr Res. 2004;38(3):249-257.
61. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010;167(suppl).
62. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, 2022. [Web]
63. American Psychological Association. (2019). Clinical practice guidelines for the treatment of depression across three age cohorts. [Web]
64. Drugs for depression. Med Lett Drugs Ther. 2023 Dec 11;65(1691):193-200.
65. Walter HJ, Bukstein OG, Abright AR, et al. Clinical Practice Guideline for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders. J Am Acad Child Adolesc Psychiatry. 2020;59(10):1107-1124.
66. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part I: Anxiety disorders. World J Biol Psychiatry. 2023;24(2):79-117.
67. Allgulander C, Mangano R, Zhang J, et al. Efficacy of Venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine. Hum Psychopharmacol. 2004;19(6):387-396.
68. Rickels K, Mangano R, Khan A. A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder. J Clin Psychopharmacol. 2004;24(5):488-496.
69. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine in social anxiety disorder. Arch Gen Psychiatry. 2005;62(2):190-198.
70. Liebowitz MR, Mangano RM, Bradwejn J, Asnis G; SAD Study Group. A randomized controlled trial of venlafaxine extended release in generalized social anxiety disorder. J Clin Psychiatry. 2005;66(2):238-247.
71. Stein MB, Pollack MH, Bystritsky A, Kelsey JE, Mangano RM. Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. Psychopharmacology (Berl). 2005;177(3):280-288.
72. Ferguson JM, Khan A, Mangano R, Entsuah R, Tzanis E. Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release. J Clin Psychiatry. 2007;68(1):58-68.
73. Stein MB, Goin MK, Pollack MH, et al. Practice guideline for the treatment of patients with panic disorder. Am J Psychiatry. 2009;166(2):1.
74. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014 Jan;123(1):202-216.
75. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, Santen RJ. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011.
76. “The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society” Advisory Panel. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause. 2023 Jun 1;30(6):573-590.
77. Williams T, Phillips NJ, Stein DJ, Ipser JC. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2022;3(3):CD002795. Published 2022 Mar 2.
78. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of Posttraumatic Stress Disorder and Acute Stress Disorder, 2023. [Web]
79. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part II: OCD and PTSD. World J Biol Psychiatry. 2023;24(2):118-134.
80. Carter J, Lacchetti C, Andersen BL, et al. Interventions to Address Sexual Problems in People With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Adaptation of Cancer Care Ontario Guideline. J Clin Oncol. 2018;36(5):492-511.
81. Resnick MJ, Lacchetti C, Penson DF; American Society of Clinical Oncology. Prostate cancer survivorship care guidelines: American Society of Clinical Oncology practice guideline endorsement. J Oncol Pract. 2015;11(3):e445-e449.
82. Management of Premenstrual Disorders: ACOG Clinical Practice Guideline No. 7. Obstet Gynecol. 2023;142(6):1516-1533.
83. American Diabetes Association Professional Practice Committee . 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2025. Diabetes Care. 2025;48(Supplement_1):S252-S265.
84. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB; American Psychiatric Association. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 2007;164(7 Suppl):5-53.
85. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.
86. Charles AC, Digre KB, Goadsby PJ, Robbins MS, Hershey A; American Headache Society. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache. 2024;64(4):333-341.
87. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of Headache, 2023. [Web]
88. Institute for Safe Medication Practices. ISMP list of confused drug names. 2024.
700. Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68.