Venlafaxine Hydrochloride Prescribing Information
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.
Age Range | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per1,000 Patients Treated |
| Increases Compared to Placebo | |
| <18 yearsold | 14 additional patients |
| 18 to 24 yearsold | 5 additional patients |
| Decreases Compared to Placebo | |
| 25 to 64 yearsold | 1 fewer patient |
| ≥65 years old | 6 fewer patients |
* Venlafaxine hydrochloride extended-release capsules are not approved in pediatric patients.
It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing venlafaxine hydrochloride extended-release capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Safety and effectiveness of venlafaxine hydrochloride extended-release capsules in pediatric patients have not been established.
Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support use in pediatric patients.
In the studies conducted in pediatric patients ages 6 to 17 years, the occurrence of blood pressure and cholesterol increases was considered to be clinically relevant in pediatric patients and was similar to that observed in adult patients [see Warnings and Precautions (5.3), Adverse Reactions (6.1)]. The following adverse reactions were also observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.
Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsules capsule’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height [see Warnings and Precautions (5.10, 5.11)]. Decreased appetite and weight loss were observed in placebo-controlled studies of pediatric patients 6 to 17 years.
In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)].
Venlafaxine hydrochloride extended-release capsules areindicated in adults for the treatment of:
- Major Depressive Disorder (MDD) [see Clinical Studies(])
14.1 Major Depressive DisorderThe efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two 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 meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, venlafaxine hydrochloride extended-release capsules also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing venlafaxine hydrochloride in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of venlafaxine hydrochloride over placebo based on the HAM-D-21 total score. The mean dose in completers was 350mg per day (study 3).
In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, once daily every morning) were randomized to continuation of their same venlafaxine hydrochloride extended-release dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued venlafaxine hydrochloride extended-release treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4).
In a second longer term trial, adult outpatients with MDD, recurrent type, who had responded (HAM-D21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAMD-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on venlafaxine hydrochloride [100 to 200 mg per day, on a twice daily schedule] were randomized to continuation of their same venlafaxine hydrochloride dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued venlafaxine hydrochloride treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5).
Table 18: Primary Efficacy Results for Studies in Major Depressive Disorder in Adults (Studies 1, 2, 3)Study numberTreatment GroupPrimary Efficacy Measure: HAM-D ScoreMean Baseline Score (SD)LS Mean Change from BaselinePlacebo Subtracted Differencea(95%CI)Study 1 Venlafaxine Hydrochloride Extended-Release (75 to 225 mg/day)* 24.5 -11.7 -4.45 (-6.66,-2.25) Placebo 23.6 -7.24 - Study 2 Venlafaxine Hydrochloride Extended-Release (75 to 225 mg/day)* 24.5 -15.11 -6.40 (-8.45,-4.34) Placebo 24.9 -8.71 Study 3 Venlafaxine hydrochloride (Immediate Release) (150 to 375 mg/day)* 28.2 (0.5) -14.9 -10.2 (-14.4,-6) Placebo 28.6 (0.6) -4.7 - SD= standard deviation; LS Mean= least-squares mean; CI= confidence interval.
aDifference (drug minus placebo) in least-squares mean change from baseline
*Doses statistically significantly superior to placebo.
- Generalized Anxiety Disorder (GAD) [see Clinical Studies(])
14.2 Generalized Anxiety DisorderThe efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD.
In one 8-week study, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied.
Two 6-month studies, one evaluating venlafaxine hydrochloride extended-release doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating venlafaxine hydrochloride extended-release capsules doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses.
Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
Table 19: Primary Efficacy Results for Studies in Generalized Anxiety Disorder in Adults (Studies 1, 2, 3, 4)Study NumberTreatment GroupPrimary Efficacy Measure: HAM-A ScoreMean BaselineScore (SD)LS Mean Changefrom Baseline (SE)*Placebo SubtractedDifferencea(95% CI)Study 1 Venlafaxine hydrochloride extended-release capsules 75 mg 24.7 -11.1 (0.95) -1.5 (-3.8, 0.8) Venlafaxine hydrochloride extended-release capsules 150 mg 24.5 -11.7 (0.87) -2.2 (-4.5, 0.1) Venlafaxine hydrochloride extended-release capsules 225 mg 23.6 -12.1 (0.81) -2.6 (-4.9, -0.3) Placebo 24.1 -9.5 (0.85) Study 2 Venlafaxine hydrochloride extended-release capsules 75 mg 23.7 -10.6 (0.82) -2.6 (-4.6, -0.5) Venlafaxine hydrochloride extended-releasecapsules 150 mg 23 -9.8 (0.86) -1.7 (-3.8, 0.3) Placebo 23.7 -8 (0.73) Study 3 Venlafaxine hydrochloride extended-release capsules 37.5 mg 26.6 (0.4) -13.8 -2.8 (-5.1, -0.6) Venlafaxine hydrochloride extended-release capsules 5 mg 26.3 (0.4) -15.5 -4.6 (-6.9, -2.3) Venlafaxine hydrochloride extended-release capsules 150 mg 26.3 (0.4) -16.4 -5.5 (-7.8, -3.1) Placebo 26.7 (0.5) -11 Study 4 Venlafaxine hydrochloride extended-release capsules 75 to 225 mg 25 -13.4 (0.79) -4.7 (-6.6, -2.9) Placebo 24.9 -8.7 (0.70) SD= standard deviation; SE= standard error; LS Mean= least-squares mean; CI= confidence interval.
aDifference (drug minus placebo) in least-squares mean change from baseline
* Doses statistically significantly superior to placebo. - Social Anxiety Disorder (SAD) [see Clinical Studies (])
14.3 Social Anxiety Disorder (Also Known as Social Phobia)The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1 to 4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5).
In these five studies, venlafaxine hydrochloride extended-release capsules werestatistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared tothe 75 mg per day group in the 6-month study.
Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
Table 20: Primary Efficacy Results for Studies in Social Anxiety Disorder in Adults(Studies 1, 2, 3, 4, 5)Study NumberTreatment GroupPrimary Efficacy Measure: LSAS ScoreMean BaselineScore (SD)LS Mean Changefrom Baseline (SE)Placebo SubtractedDifferencea(95% CI)Study 1 Venlafaxine hydrochloride extended-release capsules (75 to 225 mg)* 91.1 -31 (2.22) 11.2 (-5.3, -17.1) Placebo 86.7 -19.9 (2.22) - Study 2 Venlafaxine hydrochloride extended-release capsules (75 to 225 mg)* 90.8 -32.8 (2.69) -10.7 (-3.7,-17.6) Placebo 87.4 -22.1 (2.66) - Study 3 Venlafaxine hydrochloride extended-release capsules (75 to 225 mg)* 83.2 -36 (2.35) -16.9 (-22.6, -11.2) Placebo 83.6 -19.1 (2.40) -12.7 (-6.5, -19) Study 4 Venlafaxine hydrochloride extended-release capsules (75 to 225 mg)* 86.2 -35 (2.64) -14.6 (-21.8, -7.4) Placebo 86.1 -22.2 (2.47) Study 5 Venlafaxine hydrochloride extended-release capsules 75 mg 91.8 -38.1 (3.16) -14.6 (-21.8, -7.4) Venlafaxine hydrochloride extended-release capsules (150 to 225 mg)* 86.2 -37.6 (3.05) -14.1 (-21.3, -6.9) Placebo 89.3 -23.5 (3.08) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
aDifference (drug minus placebo) in least-squares mean change from baseline
* Doses statistically significantly superior to placebo. - Panic Disorder (PD) [see Clinical Studies (])
14.4 Panic DisorderThe efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2).
Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, venlafaxine hydrochloride extended-release capsules were statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established.
Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with venlafaxine hydrochloride extended-release capsules (75 to 225 mg per day) were randomly assigned to continue the same venlafaxine hydrochloride extended-release capsules dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued venlafaxine hydrochloride extended-release capsules experienced a statistically significantly longer time to relapse.
Table 21: Primary Efficacy Results for Studies in Panic Disorder in Adults (Studies 1 and 2)Study Treatment Group NumberPrimary Efficacy Measure: Whether Free of Full-symptom Panic AttacksPercent of patients Free ofFull symptom panic attack Adjusted Odds Ratioa to placebo Adjusted Odds Ratioa 95% Confidence Interval Study 1 Venlafaxine hydrochloride extended-release capsules 75 mg* 54.1% (85/157) 2. 268 (1.43, 3.59) Venlafaxine hydrochloride extended-release capsules 150 mg* 61.4% (97/158) 3.035 (1.91, 4.82) Placebo 34.4% (53/154) - - Study 2 Venlafaxine hydrochloride extended-release capsules 75 mg* 64.1% (100/156) 2.350 (1.46, 3.78) Venlafaxine hydrochloride extended-release capsules 225 mg* 70% (112/160) 2.890 (1.80, 4.64) Placebo 46.5% (73/157) - - a Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model. 95% CI: 95% confidence interval without adjusting for multiple dose arms.
*Doses statistically significantly superior to placebo.
Venlafaxine Hydrochloride Extended-Release Capsules, USP are available in the following strengths:
37.5 mg capsules (White to off-white colored pellets filled in hard gelatin capsule with grey opaque colored cap and pink opaque colored body imprinted ‘VFH’ on cap and ‘37.5’ on body with black ink. Free from Physical defects).
75 mg capsules (White to off-white colored pellets filled in hard gelatin capsule with pink opaque colored cap and pink opaque colored body imprinted ‘VFH’ on cap and ‘75’ on body with black ink. Free from Physical defects).
150 mg capsules (White to off-white colored pellets filled in hard gelatin capsule with sweedish orange opaque colored cap and sweedish orange opaque colored body imprinted ‘VFH’ on cap and ‘150’ on body with white ink. Free from Physical defects).
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including venlafaxine hydrochloride extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [
Available data from published epidemiologic studies on venlafaxine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes (see Data). 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 (see Clinical Considerations). There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including venlafaxine hydrochloride extended-release capsules, during pregnancy (see Clinical Considerations).
In animal studies, there was no evidence of malformations or fetotoxicity following administration of venlafaxine during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. Postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m2) the maximum human daily dose.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Women who discontinue antidepressants during pregnancy are more likely to experience arelapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depression who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Exposure to venlafaxine in mid to late pregnancy may increase the risk for preeclampsia, and exposure to venlafaxine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [
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. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SNRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Monitor neonates who were exposed to venlafaxine hydrochloride extended-release capsules in the third trimester of pregnancy for drug discontinuation syndrome (see Data).
Published epidemiological studies of pregnant women exposed to venlafaxine have not established an increased risk of major birth defects, miscarriage or other adverse developmental outcomes. Methodological limitations may both fail to identify true findings and also identify findings that are not true.
Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted [adj] RR 1.57, 95% confidence interval [CI] 1.29-1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg per day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10-20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg per day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders.
Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24 [95% CI 1.69-2.97]). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64-1.76). The results of this study may be confounded by the effects of depression.
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2basis.
When desvenlafaxine succinate, the major metabolite of venlafaxine, was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no fetal malformations were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day.
Venlafaxine hydrochloride extended-release capsules are contraindicated in patients:
- with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation [see Adverse Reactions ()].
6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of venlafaxine hydrochloride extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole– Anaphylaxis, angioedemaCardiovascular System– QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathyDigestive System– PancreatitisHemic/Lymphatic System– Mucous membrane bleeding [see Warnings and Precautions ], blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopeniaMetabolic/Nutritional– Hyponatremia [see Warnings and Precautions ], Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions ], abnormal liver function tests, hepatitis, prolactin increasedMusculoskeletal– RhabdomyolysisNervous System– Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ], serotonergic syndrome [see Warnings and Precautions ], delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesiaRespiratory, Thoracic and Mediastinal Disorders– Anosmia, dyspnea, hyposmia, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions ]Skin and Appendages– Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiformeSpecial Senses– Angle-closure glaucoma [see Warnings and Precautions ] - taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome [see Dosage and Administration (), Warnings and Precautions (
2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) AntidepressantAt least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of venlafaxine hydrochloride extended-release capsules. In addition, at least 7 days must elapse after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI antidepressant [see Contraindications ].
)].5.2 Serotonin SyndromeSerotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine hydrochloride extended-release capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications , Drug Interactions ]. Serotonin syndrome can also occur when these drugs are used alone.
Serotonin syndrome signs and symptoms 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of venlafaxine hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate venlafaxine hydrochloride extended-release capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine hydrochloride extended-release capsules, discontinue venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI [see Contraindications , Drug Interactions , Contraindications and Warnings and Precautions ]
Other Serotonergic Drugs Clinical ImpactConcomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. InterventionMonitor for symptoms of serotonin syndrome when venlafaxine hydrochloride extended-release capsules is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of venlafaxine hydrochloride extended-release capsules and/or concomitant serotonergic drugs [see Dosage and Administration and Warnings and Precautions ]. Drugs that Interfere with Hemostasis Clinical ImpactConcomitant use of venlafaxine hydrochloride extended-release capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine hydrochloride extended-release capsules on the release of serotonin by platelets. InterventionClosely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when venlafaxine hydrochloride extended-release capsules is initiated or discontinued [see Warnings andPrecautions ]. Effect of CYP3A Inhibitors Clinical ImpactConcomitant use of a CYP3A inhibitor increases the Cmax and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology ], which may increase the risk of toxicity of venlafaxine hydrochloride extended-release capsules InterventionConsider reducing the dose of venlafaxine hydrochloride extended-release capsules. CYP2D6 Substrates Clinical ImpactConcomitant use of venlafaxine hydrochloride increases Cmaxand AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology ]. InterventionConsider reduction in dose of concomitant CYP2D6 substrates
- Serotonin Syndrome:Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue venlafaxine hydrochloride extended-release capsules and serotonergic agents and initiate supportive treatment (,4 CONTRAINDICATIONS
Venlafaxine hydrochloride extended-release capsules are contraindicated in patients:
- with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation [see Adverse Reactions ].
- taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome [see Dosage and Administration , Warnings and Precautions , and Drug Interactions ].
- Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the venlafaxine hydrochloride extended-release capsules formulation .
- Concomitant use of monoaminoxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI .
).5.2 Serotonin SyndromeSerotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine hydrochloride extended-release capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications , Drug Interactions ]. Serotonin syndrome can also occur when these drugs are used alone.
Serotonin syndrome signs and symptoms 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of venlafaxine hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate venlafaxine hydrochloride extended-release capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine hydrochloride extended-release capsules, discontinue venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI [see Contraindications , Drug Interactions , Contraindications and Warnings and Precautions ]
Other Serotonergic Drugs Clinical ImpactConcomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. InterventionMonitor for symptoms of serotonin syndrome when venlafaxine hydrochloride extended-release capsules is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of venlafaxine hydrochloride extended-release capsules and/or concomitant serotonergic drugs [see Dosage and Administration and Warnings and Precautions ]. Drugs that Interfere with Hemostasis Clinical ImpactConcomitant use of venlafaxine hydrochloride extended-release capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine hydrochloride extended-release capsules on the release of serotonin by platelets. InterventionClosely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when venlafaxine hydrochloride extended-release capsules is initiated or discontinued [see Warnings andPrecautions ]. Effect of CYP3A Inhibitors Clinical ImpactConcomitant use of a CYP3A inhibitor increases the Cmax and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology ], which may increase the risk of toxicity of venlafaxine hydrochloride extended-release capsules InterventionConsider reducing the dose of venlafaxine hydrochloride extended-release capsules. CYP2D6 Substrates Clinical ImpactConcomitant use of venlafaxine hydrochloride increases Cmaxand AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology ]. InterventionConsider reduction in dose of concomitant CYP2D6 substrates - Elevated Blood Pressure:Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ().
5.3 Elevated Blood PressureIn controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension [see Adverse Reactions ].
Monitor blood pressure before initiating treatment with venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with venlafaxine hydrochloride extended-release capsules. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with venlafaxine hydrochloride extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure.
Across all clinical studies with venlafaxine hydrochloride, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥15 mmHg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients inthe venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥ 20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥ 180 mmHg, compared to 0.3% of patients in the placebo groups [see Adverse Reactions (6.1)]. Treatment with venlafaxine hydrochloride extended-release capsules wasassociated with sustained hypertension (defined as SDBP ≥ 90 mm Hg and ≥ 10 mmHg above baseline for three consecutive on-therapy visits [seeAdverse Reactions ]. An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg per dayin clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
- Increased Risk of Bleeding:Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk ().
5.4 Increased Risk of BleedingDrugs that interfere with serotonin reuptake inhibition, including venlafaxine hydrochloride extended-release capsules may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [
see Use in Specific Populations].Inform patients about the increased risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing venlafaxine hydrochloride extended-release capsules.
- Angle-Closure Glaucoma:Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles, treated with antidepressants. ().
5.5 Angle-Closure GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine hydrochloride extended-release capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including venlafaxine hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles.
- Activation of Mania or Hypomania:Screen patients for bipolar disorder ().
5.6 Activation of Mania or HypomaniaIn patients with bipolar disorder, treating a depressive episode with venlafaxine hydrochloride extended-release capsules or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in venlafaxine hydrochloride extended-release capsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with venlafaxine hydrochloride extended-release capsules, screen for any personal or family history of bipolar disorder, mania, or hypomania.
Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Hydrochloride Extended-Release Capsules Treated Patients in the Premarketing StudiesIndicationVenlafaxine Hydrochloride Extended-ReleaseCapsulesPlaceboMDD 0.3 0.0 GAD 0 0 0.2 SAD 0.2 0.0 PD 0.1 0.0 - Discontinuation Syndrome:Taper dose and monitor for discontinuation symptoms ().
5.7 Discontinuation SyndromeDiscontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms 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 (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.
There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in venlafaxine hydrochloride extended-release capsules dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of venlafaxine hydrochloride extended-release capsules.
During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures.
Patients should be monitored for these symptoms when discontinuing treatment with venlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months [see Dosage and Administration ].
- Seizures:Can occur. Use cautiously in patients with seizure disorder ().
5.8 SeizuresCases of seizure have been reported with venlafaxine therapy. venlafaxine hydrochloride extended-release capsules have not been systematically evaluated in patients with seizure disorder. venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder.
- Hyponatremia:Can occur in association with SIADH ().
5.9 HyponatremiaHyponatremia can occur as a result of treatment with SNRIs, including venlafaxine hydrochloride extended-release capsules. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, orthose who are otherwise volume-depleted, may be at greater risk[see Use in Specific Populations and Clinical Pharmacology ]. Consider discontinuation of venlafaxine hydrochloride extended-release capsules in patients with symptomatic hyponatremia, and institute appropriate medical intervention.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which maylead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Interstitial Lung Disease and Eosinophilic Pneumonia:Can occur ().
5.12 Interstitial Lung Disease and Eosinophilic PneumoniaInterstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in venlafaxine hydrochloride extended-release capsules treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-releasecapsules should be considered.
- Sexual Dysfunction: Venlafaxine hydrochloride extended-release capsules may cause symptoms of sexual dysfunction ().
5.13 Sexual DysfunctionUse of SNRIs, including venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction [see Adverse Reactions ]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of venlafaxine hydrochloride extended-release capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.