Venlafaxine Prescribing Information
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD) or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
| Increases Compared to Placebo | |
| < 18 | 14 additional cases |
| 18 to 24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25 to 64 | 1 fewer case |
| ≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. It should be noted that venlafaxine extended-release tablets are not approved for use in treating bipolar depression.
Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
| Warning and Precautions ( 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine extended-release tablets, 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, tryptophan, meperidine, methadone, busipirone, 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 and 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 extended-release tablets with MAOIs is contraindicated. In addition, do not initiate venlafaxine extended-release tablets 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 a MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine extended-release tablets, discontinue venlafaxine extended-release tablets before initiating treatment with the MAOI [see Contraindications , Drug Interactions ]. Monitor all patients taking venlafaxine extended-release tablets for the emergence of serotonin syndrome. Discontinue treatment with venlafaxine extended-release tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of venlafaxine extended-release tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.13 Increased Risk of Bleeding SSRIs and SNRIs, including venlafaxine extended-release tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin and other anticoagulants 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 ]. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis and petechiae to life-threatening hemorrhages.Patients should be cautioned about the increased risk of bleeding associated with the concomitant use of venlafaxine extended-release tablets and NSAIDs, aspirin or other drugs that affect coagulation. | 8/2023 |
Venlafaxine extended-release tablets are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for:
- Major Depressive Disorder (MDD) ()1.1 Major Depressive Disorder
Venlafaxine extended-release tablets are indicated for the treatment of major depressive disorder (MDD).
Efficacy of venlafaxine in MDD was shown in both short-term trials and a longer-term trial in MDD
[see Clinical Studies ].A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
- Social Anxiety Disorder (SAD) ()1.2 Social Anxiety Disorder
Venlafaxine extended-release tablets are indicated for the treatment of Social Anxiety Disorder (SAD), also known as Social Phobia, as defined in DSM-IV.
Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning or social activities or relationships or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
Efficacy of venlafaxine extended-release in the treatment of SAD was established in short-term SAD trials
[see Clinical Studies ].
Venlafaxine extended-release tablets should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each tablet should be swallowed whole with fluid and not divided, crushed, chewed or placed in water.
Venlafaxine extended-release tablets, 37.5 mg are white to off-white round, biconvex, coated tablets with release portal and imprinted with 1348.
Venlafaxine extended-release tablets, 75 mg are white to off-white round, biconvex, coated tablets with release portal and imprinted with 1349.
Venlafaxine extended-release tablets, 150 mg are white to off-white round, biconvex, coated tablets with release portal and imprinted with 1350.
Venlafaxine extended-release tablets, 225 mg are white to off-white round, biconvex, coated tablets with release portal and imprinted with 1352.
- Pregnancy:Use during pregnancy only if clearly needed. Neonates exposed to venlafaxine in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Benefits and risk of venlafaxine use in the third trimester should be carefully considered. (;2.3 Special PopulationsTreatment of Pregnant Women During the Third Trimester
Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding
[see Use in Specific Populations ].When treating pregnant women with venlafaxine extended-release tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50% and individualization of dosing may be desirable in some patients.Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 mL/min to 70 mL/min) compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 25% to 50%.In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
Elderly PatientsNo dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
)8.1 PregnancyBased 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
[see Warnings and Precautions and Clinical Considerations].Teratogenic EffectsVenlafaxine 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/m2basis.
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. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Non-Teratogenic EffectsNeonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors) or SSRIs (Selective Serotonin Reuptake Inhibitors), 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, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and 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 ].When treating a pregnant woman with venlafaxine extended-release tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.Maternal Adverse ReactionsExposure to venlafaxine extended-release tablets in mid to late pregnancy may increase the risk of preeclampsia, and exposure to venlafaxine extended-release tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage
[see Warnings and Precautions ]. - Nursing:Potential for serious adverse reactions in the infant. Discontinue nursing or drug, considering the importance of the drug to the mother. ()
8.3 Nursing MothersVenlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from venlafaxine extended-release tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
- Pediatric use:Not approved for use in pediatric patients. When considering use in a child or adolescent, balance potential risks with clinical need. ()
8.4 Pediatric UseSafety and effectiveness in the pediatric population have not been established
[see Boxed Warning and Warnings and Precautions ].Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in another disorder in 793 pediatric patients have been conducted with venlafaxine hydrochloride extended-release capsules and the data were not sufficient to support a claim for use in pediatric patients.
Anyone considering the use of venlafaxine extended-release tablets in a child or adolescent must balance the potential risks with the clinical need.
Although no studies have been designed to primarily assess impact of venlafaxine hydrochloride extended-release capsules on the growth, development and maturation of children and adolescents, the studies that have been done suggest that venlafaxine extended-release tablets may adversely affect weight and height
[see Warnings and Precautions ].Should the decision be made to treat a pediatric patient with venlafaxine extended-release tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of venlafaxine extended-release tablets treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.In the studies conducted in pediatric patients (ages 6 to 17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients
[see Warnings and Precautions ]. - Hepatic impairment:Reduction of total daily dose by 50% recommended in patients with mild to moderate impairment. In patients with cirrhosis, further reduction may be necessary and dosing individualization may be desirable. (;2.3 Special PopulationsTreatment of Pregnant Women During the Third Trimester
Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding
[see Use in Specific Populations ].When treating pregnant women with venlafaxine extended-release tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50% and individualization of dosing may be desirable in some patients.Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 mL/min to 70 mL/min) compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 25% to 50%.In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
Elderly PatientsNo dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
)8.6 Patients with Hepatic ImpairmentIn patients with cirrhosis of the liver, the clearances of venlafaxine and its active metabolite (ODV) were decreased, thus prolonging the elimination half-lives of these substances. A large degree of intersubject variability was noted
[see Clinical Pharmacology ].A lower dose and individualization of dosing may be necessary[see Dosage and Administration ].Venlafaxine extended-release tablets, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients. - Renal impairment:Reduction of daily dose by 25% to 50% recommended. Dosing individualization may be necessary. (;2.3 Special PopulationsTreatment of Pregnant Women During the Third Trimester
Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding
[see Use in Specific Populations ].When treating pregnant women with venlafaxine extended-release tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50% and individualization of dosing may be desirable in some patients.Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 mL/min to 70 mL/min) compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 25% to 50%.In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
Elderly PatientsNo dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
)8.7 Patients with Renal ImpairmentIn patients with renal impairment (GFR=10 mL/min to 70 mL/min), the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances
[see Clinical Pharmacology ].It is recommended that the total daily dose be reduced by 25% to 50% in patients with renal impairment. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%[see Dosage and Administration ],venlafaxine extended-release tablets, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients. - Hemodialysis:Reduction of daily dose by 50%. (;2.3 Special PopulationsTreatment of Pregnant Women During the Third Trimester
Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding
[see Use in Specific Populations ].When treating pregnant women with venlafaxine extended-release tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50% and individualization of dosing may be desirable in some patients.Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 mL/min to 70 mL/min) compared with normal subjects
[see Use in Specific Populations and Clinical Pharmacology ],it is recommended that the total daily dose be reduced by 25% to 50%.In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
Elderly PatientsNo dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
)8.7 Patients with Renal ImpairmentIn patients with renal impairment (GFR=10 mL/min to 70 mL/min), the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances
[see Clinical Pharmacology ].It is recommended that the total daily dose be reduced by 25% to 50% in patients with renal impairment. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%[see Dosage and Administration ],venlafaxine extended-release tablets, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients.