Venlafaxine - Venlafaxine tablet, Extended Release 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.
| *Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. | |
Age Range | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated |
| Increases Compared to Placebo | |
| < 18 years old | 14 additional patients |
| 18–24 years old | 5 additional patients |
| Decreases Compared to Placebo | |
| 25–64 years old | 1 fewer patient |
| ≥ 65 years old | 6 fewer 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 Extended-Release Tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Safety and effectiveness of Venlafaxine Extended-Release Tablets 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 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
Although no studies have been designed to primarily assess Venlafaxine Extended-Release Tablet’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine extended-release capsules may adversely affect weight and height
In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients
Warnings and Precautions (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, 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 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 an 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 Dosage and Administration , 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. Drugs that interfere with serotonin reuptake inhibition, including Venlafaxine Extended-Release Tablets, 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 Extended-Release Tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine Extended-Release Tablets. | 8/2023 |
Venlafaxine Extended-Release Tablets are indicated in adults for the treatment of:
- Major depressive disorder (MDD)
- Generalized Anxiety Disorder (GAD)
Extended-release tablets: 112.5 mg, white, round, biconvex tablet, with “ALM” over “632” printed in black ink on one side, and plain on the other side.
- Pregnancy: Third trimester use may increase risk for symptoms of poor neonatal adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ().
8.1 PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including Venlafaxine Extended-Release Tablets, 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/research/pregnancyregistry/antidepressants.
Risk SummaryBased 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].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 exposure to SNRIs, including Venlafaxine Extended-Release Tablets, 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/m2basis. 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.
Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskWomen who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Maternal Adverse ReactionsExposure to Venlafaxine Extended-Release Tablets in mid to late pregnancy may increase the risk for preeclampsia, and exposure to Venlafaxine Extended-Release Tablets in the month before near delivery may be associated with an increased the risk for of postpartum hemorrhage
[see Warnings and Precautions ].Fetal/Neonatal Adverse ReactionsNeonates 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 ]. Monitor neonates who were exposed to Venlafaxine Extended-Release Tablets in the third trimester of pregnancy for drug discontinuation syndrome.DataHuman DataPublished epidemiological studies of pregnant women exposed to venlafaxine have not established an increase 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.
Animal DataVenlafaxine 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.
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 Extended-Release Tablets are contraindicated in patients:
- with known hypersensitivity to venlafaxine besylate, venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in Venlafaxine Extended-Release Tablets [see Adverse Reactions (.)]
6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of venlafaxine 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 (5.9)], abnormal liver function tests, hepatitis, prolactin increasedMusculoskeletal– RhabdomyolysisNervous system– Neuroleptic Malignant Syndrome (NMS)[see Warnings and Precautions ], serotonergic syndrome[see Warnings and Precautions (5.2)], 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 increased risk of serotonin syndrome [see Dosage and Administration (.), Warnings and Precautions (
2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) AntidepressantAt least 14 days must elapse between discontinuation of an MAOI (intended to treat psychiatric disorders) and initiation of therapy with Venlafaxine Extended-Release Tablets. In addition, at least 7 days should be allowed after stopping Venlafaxine Extended-Release Tablets before starting an MAOI intended to treat psychiatric disorders
[see Contraindications , Warnings and Precautions , and Drug Interactions ].), Drug Interactions (5.2 Serotonin SyndromeSerotonin-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, 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 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 an 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 Dosage and Administration , 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.
)]7.1 Drugs Having Clinically Important Interactions with Venlafaxine Extended-Release TabletsTable 13: Clinically Significant Drug Interactions with Venlafaxine Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI)Clinical ImpactConcomitant use of SNRIs, including Venlafaxine Extended-Release Tablets, with MAOIs increases the risk of serotonin syndrome. InterventionConcomitant use of Venlafaxine Extended-Release Tablets is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration , Contraindications , and Warnings and Precautions ].Other Serotonergic DrugsClinical ImpactConcomitant use of Venlafaxine Extended-Release Tablets 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 Extended-Release Tablets is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Venlafaxine Extended-Release Tablets and/or concomitant serotonergic drugs [see Dosage and Administration , Warnings and Precautions ].AlcoholClinical ImpactBased on an in vitrostudy, alcohol increases the release rate of Venlafaxine Extended-Release Tablets[see Clinical Pharmacology ].InterventionAvoid concomitant use of alcohol during treatment with Venlafaxine Extended-Release Tablets. Drugs that Interfere with HemostasisClinical ImpactConcomitant use of Venlafaxine Extended-Release Tablets with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. InterventionClosely monitor patients receiving an antiplatelet or anticoagulant drug for bleeding when Venlafaxine Extended-Release Tablets is initiated or discontinued [see Warnings and Precautions ].CYP3A InhibitorsClinical ImpactConcomitant use of Venlafaxine Extended-Release Tablets with a CYP3A inhibitor increases the Cmaxand AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology ], which may increase the risk of toxicity of venlafaxine.InterventionConsider reducing the dose of Venlafaxine Extended-Release Tablets. CYP2D6 SubstratesClinical ImpactConcomitant use of Venlafaxine Extended-Release Tablets with a CYP2D6 substrate increases Cmaxand AUC of the CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology ].InterventionConsider reduction in dose of concomitant CYP2D6 substrates.