Venlafaxine 225 mg Tablet, Extended Release, 90-count — NDC 43598-944-90 (Billing 43598-0944-90)
This is a package of 90 tablets of Venlafaxine 225 mg Tablet, Extended Release from Dr. Reddy's Laboratories Inc., marketed since Sep 2021 and currently FDA-listed; retail pharmacies pay about $0.4712 per tablet (NADAC).
Past resolved recalls for this product (1)
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 064447
- GCN: 14354
- GPI-14 (Medi-Span): 58180090107540
- HICL (First Databank): 008847
- AHFS class code: 28:16.04.16
- RxCUI (RxNorm): 808744
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Serotonin and Norepinephrine Reuptake Inhibitor class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
- It treats major depressive disorder. Depending on the product, it is also used for social anxiety disorder, generalized anxiety disorder and panic disorder. Your pharmacist can con...
- Take extended-release forms once a day with food, at about the same time each day. Swallow tablets and capsules whole. A capsule can be opened onto applesauce if swallowing is hard...
- Nausea, sleepiness, dry mouth, sweating, constipation and loss of appetite are common. Some people have sexual side effects. Call your doctor if side effects are severe or don’t ea...
- Please don’t stop suddenly. Stopping or cutting the dose quickly can cause dizziness, nausea, anxiety, insomnia and electric-shock feelings. Your prescriber will lower the dose gra...
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Venlafaxine — tap one for details:
Venlafaxine may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.471 | $42.41 / 90 tablets |
| Medicaid paysCMS SDUD · 12 mo | $1.11 | $100.02 / 90 tablets |
| Medicare drug plans payPart D · Q2 2026 | $2.33 | $209.52 / 90 tablets |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Marketing end | Status |
|---|---|---|---|---|---|---|
| 43598-0944-30 43598-944-30 Main listing | 30 TABLET, EXTENDED RELEASE in 1 BOTTLE | $0.4712 / ea | $14.14 | 2021-09-20 | — | Active |
| 43598-0944-90 You're viewing this | 90 TABLET, EXTENDED RELEASE in 1 BOTTLE | $0.4712 / ea | $42.41 | 2021-09-20 | — | Active |
You're viewing the largest of 2 pack sizes for this product.
This pack effectively ties for the lowest per-ea cost of the 2 priced pack sizes ($0.4712 NADAC).
This pack accounts for about 4.3% of this product's recent Medicaid fills; most go to the 30 tablets pack. See all packs ↓
Pack size FAQ
What quantity is in this package?
How does this package differ from NDC 43598-0944-30?
What NDC number is used to bill for this package of Venlafaxine 225 mg Tablet, Extended Release?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Venlafaxine Hydrochloride 225 mg 13811-0715-30 | Trigen | 30 tablets | $0.471 | AB | Discontinued | — |
| Venlafaxine 225 mg 27241-0224-30 | Ajanta | 30 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine Hydrochloride 225 mg 31722-0126-30 | Camber | 30 tablets | $0.471 | AB | Availability likely | — |
| venlafaxine hydrochloride, extended release 225 mg 42799-0963-01 | Edenbridge | 30 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine 225 mgthis 43598-0944-90 | Dr. | 90 tablets | $0.471 | AB | Availability likely | — |
| venlafaxine hydrochloride 225 mg 62135-0531-30 | Chartwell | 30 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine Hydrochloride 225 mg 64980-0581-03 | Rising | 30 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine 225 mg 67877-0729-30 | Ascend | 30 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine Hydrochloride 225 mg 68001-0499-04 | BluePoint | 30 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine Hydrochloride 225 mg 69367-0418-09 | Westminster | 90 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine 225 mg 72241-0077-04 | Modavar | 90 tablets | $0.471 | AB | Availability likely | — |
| Venlafaxine Hydrochloride 225 mg 47335-0794-08 | Sun | 100 tablets | — | — | FDA listed | — |
| Venlafaxine 225 mg 70710-1352-01 | Zydus | 100 tablets | — | AB | FDA listed | — |
| Venlafaxine 225 mg 70771-1652-01 | Zydus | 100 tablets | — | AB | FDA listed | — |
| Venlafaxine 225 mg 71209-0089-01 | Cadila | 30 tablets | — | AB | FDA listed | — |
| Venlafaxine Hydrochloride 225 mg 72865-0200-30 | XLCare | 30 tablets | — | AB | FDA listed | — |
| Venlafaxine Hydrochloride 225 mg 75834-0219-00 | Nivagen | 1000 tablets | — | AB | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of venlafaxine extended-release tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber.
Venlafaxine extended-release tablets are not approved for use in pediatric patients. [ See Warnings and Precautions (5.1) and Patient Counseling Information (17.1 )] WARNING: Suicidality and Antidepressants See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders. Venlafaxine extended-release tablets are not approved for use in pediatric patients.
(5.1)
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Venlafaxine extended-release tablets are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: • Major Depressive Disorder (MDD) (1.1) • Social Anxiety Disorder (SAD) (1.2)
1.1Major 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 (14.1) ] . 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.
1.2Social 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 tablets in the treatment of SAD was established in short-term SAD trials [ see Clinical Studies (14.2)] .
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION 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. • Initial Treatment (2.1) Indication Starting Dose Dose Increase Maximum Dose Major Depressive Disorder 75 mg/day (in some patients, 37.5 mg/day for 4 to 7 days) 75 mg/day increments at intervals of 4 days or longer 225 mg/day Social Anxiety Disorder 75 mg/day No benefit at higher doses 75 mg/day • Venlafaxine extended-release tablets should be taken as a single daily dose with food in either the morning or evening at the same time each day.
(2) • Discontinuation: Gradual; individualized as necessary. (2.4)
2.1Initial Treatment Major Depressive Disorder For most patients, the recommended starting dose for venlafaxine extended-release tablets is 7 5 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of venlafaxine hydrochloride extended-release capsules in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day.
While the relationship between dose and antidepressant response for venlafaxine hydrochloride extended-release capsules has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4.
In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day [ see Clinical Studies (14) ]. It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for venlafaxine hydrochloride immediate-release tablets, more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day).
Whether or not higher doses of venlafaxine extended-release tablets are needed for more severely depressed patients is unknown; however, the experience with venlafaxine hydrochloride extended-release capsule doses higher than 225 mg/day is very limited. Social Anxiety Disorder (Social Phobia) The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.
2.2Maintenance Treatment There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder should be treated with venlafaxine extended-release tablets. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended-release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg per day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated.
A second longer-term study has demonstrated the efficacy of venlafaxine hydrochloride immediate-release tablets in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine hydrochloride immediate-release tabl… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Venlafaxine extended-release tablets are available as: - 150 mg tablets (White to off white, round shaped, coated tablet, debossed with “AC 406” on one side and plain on the other side) - 225 mg tablets (White to off white, round shaped, coated tablet, and debossed with “AC" on one side and “407” on the other side) • 150 mg, and 225 mg tablets
⛔ Contraindications ▾
4 CONTRAINDICATIONS • Serotonin Syndrome and MAOIs: Do not use MAOI’s intended to treat psychiatric disorders with venlafaxine extended-release tablets or within 7 days of stopping treatment with venlafaxine extended-release tablets. Do not use venlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start venlafaxine extended-release tablets in a patient who is being treated with linezolid or intravenous methylene blue (4.1).
4.1Monoamine Oxidase Inhibitors (MAOIs) The use of MAOI’s intended to treat psychiatric disorders with venlafaxine extended-release tablets or within 7 days of stopping treatment with venlafaxine extended-release tablets is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. [ see Dosage and Administration (2.6) and Warnings and Precautions (5.2) ]. Starting venlafaxine extended-release tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [ see Dosage and Administrations (2.7) and Warnings and Precautions (5.2) ] .
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome : Serotonin syndrome has been reported with SSRIs and SNRIs, including venlafaxine extended-release tablets, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue venlafaxine extended-release tablets and serotonergic agents and initiate supportive treatment. If concomitant use of venlafaxine extended-release tablets with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
(5.2). • Suicidality: Monitor for clinical worsening and suicide risk. (5.1) • Sustained hypertension may occur. Blood pressure monitoring recommended.
(5.3) • Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.4) • Abrupt discontinuation or dose reduction: Discontinuation symptoms may occur (generally self-limiting; serious symptoms possible). Dose reduction recommended to be gradual.
(5.5) • Activation of Mania/Hypomania has occurred. (5.10) • Symptomatic hyponatremia may occur. (5.11) • Seizures have been reported.
Use with caution in patients with seizure history. (5.12) • Abnormal bleeding (most commonly ecchymosis) has been reported. (5.13) • Serum cholesterol: Clinically relevant cholesterol increases may occur.
Cholesterol measurements should be considered during long-term therapy. (5.14) • Interstitial lung disease and eosinophilic pneumonia have been reported. (5.15) • Sexual Dysfunction: Venlafaxine extended-release tablets may cause symptoms of sexual dysfunction (5.18)
5.1Clinical Worsening and Suicide Risk 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 4400 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 1000 patients treated) a… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS Major Depressive Disorder - Adverse events in short-term studies that occurred in at least 5% of the patients receiving venlafaxine extended-release capsules and at a rate at least twice that of the placebo group were abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. Social Anxiety Disorder - Adverse events in short-term studies that occurred in at least 5% of the patients receiving venlafaxine extended-release capsules and at a rate at least twice that of the placebo group were asthenia, gastrointestinal complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and abnormal vision.
To report SUSPECTED ADVERSE REACTIONS, contact Appco Pharma LLC at 1-855-672-7726 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Studies Experience Data Sources The information included in subsection "Adverse Findings Observed in Short-Term, Placebo- Controlled Studies with Venlafaxine Hydrochloride Extended-Release Capsules" is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), and on data up to 12 weeks from a pool of two controlled clinical trials in Social Anxiety Disorder. Information on additional adverse reactions associated with venlafaxine hydrochloride extended-release capsules in the entire development program for the formulation and with venlafaxine hydrochloride immediate-release tablets is included in the subsection "Other Adverse Reactions Observed During the Premarketing Evaluation of Venlafaxine Hydrochloride Immediate-Release Tablets and Venlafaxine Hydrochloride Extended-Release Capsules" [ see also Warnings and Precautions (5) ].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Venlafaxine Hydrochloride Extended-Release Capsules Adverse Reactions Associated with Discontinuation of Treatment Major Depressive Disorder: Approximately 11% of the 357 patients who received venlafaxine hydrochloride extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse reaction, compared with 6% of the 285 placebo-treated patients in those studies.
Adverse reactions that led to treatment discontinuation in a least 2% of drug-treated patients were nausea, dizziness, and somnolence. Social Anxiety Disorder: Approximately 17% of the 277 patients who received venlafaxine hydrochloride extended-release capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse reaction, compared with 5% of the 274 placebo-treated patients in those studies. Adverse reactions that led to treatment discontinuation in a least 2% of drug-treated patients were nausea, insomnia, impotence, headache, dizziness, and somnolence.
Adverse Reactions Occurring at an Incidence of 5% or More Major Depressive Disorder : Note in particular the following adverse reactions that occurred in at least 5% of the patients receiving venlafaxine hydrochloride extended-release capsules and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication (see Table 6): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating.
In the two U.S. placebo-controlled trials, the following additional reac… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS • MAOI’s: concomitant use contraindicated (4). Avoid MAOI’s 14 days before starting venlafaxine and 7 days after stopping venlafaxine (5.2). • Cimetidine: Caution in patients with pre-existing hypertension, in elderly patients and patients with hepatic dysfunction. (7.2) • Haloperidol: Increase in Haloperidol AUC and Cmax.
(7.4) • Ketoconazole: Increase in venlafaxine and O-desmethylvenlafaxine AUC and Cmax. Caution when using venlafaxine with substances that inhibit both CYP2D6 and CYP3A4. (7.7) • Metoprolol: Possibly reduced blood-pressure lowering effect despite increased metoprolol plasma levels.
Caution should be exercised with co-administration of venlafaxine and metoprolol. (7.8) • CNS-active drugs: Caution when using venlafaxine with such drugs. (7.10) • Serotonergic drugs (e.g., triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St.
John's Wort): Potential for serotonin syndrome. Careful patient observation advised. (7.10) • Tryptophan supplements: Concomitant use not recommended.
(7.10)
7.1Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.
7.2Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C max ) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine.
The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.
7.3Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.
7.4Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged. The mechanism explaining this finding is unknown.
7.5Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS- Active Drugs, below).
7.6Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine extended-release tablets to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
7.7Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inh… [Excerpted — this section continues on DailyMed.]
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS • 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; 8.1) • Nursing: Potential for serious adverse reactions in the infant. Discontinue nursing or drug, considering the importance of the drug to the mother. (8.3) • 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) • 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; 8.6) • Renal impairment: Reduction of daily dose by 25 to 50% recommended. Dosing individualization may be necessary. (2.3; 8.7) • Hemodialysis: Reduction of daily dose by 50%.
(2.3; 8.7)
8.1Pregnancy 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 [ see Warnings and Precautions (5.13) and Clinical Considerations ]. Teratogenic Effects 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/m 2 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/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m 2 basis.
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 Effects Neonates 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 (5.2) ]. 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 Reactions Exposure 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 (5.13)].
8.2Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown.
8.3Nursing Mothers Venlafaxine 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 disconti… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy 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 [ see Warnings and Precautions (5.13) and Clinical Considerations ]. Teratogenic Effects 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/m 2 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/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m 2 basis.
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 Effects Neonates 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 (5.2) ]. 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 Reactions Exposure 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 (5.13)].
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness in the pediatric population have not been established [ see BOXED WARNING and Warnings and Precautions (5.1) ]. 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 (5.7 , 5.8 , and 5.9) ]. 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 (5.3 and 5.14) ].
🧓 Geriatric Use ▾
8.5Geriatric Use Approximately 4% (14/357) and 2% (6/277) of patients treated with venlafaxine hydrochloride extended-release capsules in placebo-controlled premarketing major depressive disorder and Social Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 patients treated with venlafaxine hydrochloride immediate-release tablets in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients.
However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction[ see Warnings and Precautions (5.11) ]. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [ see Clinical Pharmacology (12.3) ].
No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction [ see Dosage and Administration(2.3) ].
🆘 Overdosage ▾
10 OVERDOSAGE
10.1Human Experience Among the patients included in the premarketing evaluation of venlafaxine hydrochloride extended-release capsules, there were 2 reports of acute overdosage with venlafaxine hydrochloride extended-release capsules in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of venlafaxine hydrochloride extended-release capsules and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects.
The other patient took 2.85 g of venlafaxine hydrochloride extended-release capsules. This patient reported paresthesia of all four limbs but recovered without sequelae. There were no reports of acute overdose with venlafaxine hydrochloride extended-release capsules in Social Anxiety Disorder trials.
Among the patients included in the premarketing evaluation with venlafaxine hydrochloride immediate-release tablets, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g.
The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae.
Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline.
Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported reactions in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting.
Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients.
The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine extended-release tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
10.2Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
Activated charcoal should be administer… [Excerpted — this section continues on DailyMed.]
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.
12.2Pharmacodynamics Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV) have no significant affinity for muscarinic cholinergic, H 1 -histaminergic, or α 1 -adrenergic receptors in vitro . Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
12.3Pharmacokinetics Steady-state concentrations of venlafaxine and O-desmethylvenlafaxine (ODV) in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. The mean ± SD apparent elimination half-life for venlafaxine and ODV after administration of 75 mg venlafaxine extended-release tablets under fed conditions were 10.7±3.2 hours and 12.5±3.0 hours respectively.
Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption and Distribution Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the only major active metabolite.
On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of 75 mg venlafaxine extended-release tablets under fed conditions resulted in mean ± SD venlafaxine C max of 26.9 ± 13.4 ng/mL and AUC of 1536.3 ± 496.8 ng·hr/mL.
T max was 6.3 ± 2.3 hours. ODV mean ± SD C max , AUC, T max after administration of 75 mg venlafaxine extended-release tablets under fed conditions were 97.9 ± 29.4 ng/mL, 2926.0 ± 746.1 ng·hr/mL, and 11.6 ± 2.9 hours, respectively. Administration of venlafaxine hydrochloride extended-release capsules (150 mg q24 hours) generally resulted in lower C max (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later T max (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (C max 's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV).
When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release form of venlafaxine, the exposure to both venlafaxine and ODV would be similar for the two treatments. Venlafaxine extended-release tablets would, therefore, provide a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the pharmacokinetic parameters AUC, C max , and T max of venlafaxine or its active metabolite, ODV, after administration of venlafaxine extended-release tablets.
Time of administration (AM vs PM) would not affect the pharmacokinetics of venlafaxine and ODV. Equal doses of venlafaxine hydrochloride extended-release tablets are bioequivalent to Effexor XR capsules when administered under fed conditions. Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites.
In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The diff… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Venlafaxine extended-release tablets 150 mg are White to off white, round shaped, coated tablet, debossed with “AC 406” on one side and plain on the other side. They are supplied as follows: Unit of Use Bottles of 30 Tablets NDC – 43598-943-30 Unit of Use Bottles of 90 Tablets NDC – 43598-943-90 Venlafaxine extended-release tablets 225 mg are White to off white, round shaped, coated tablet, and debossed with “AC” on one side and "407" on the other side. They are supplied as follows: Unit of Use Bottles of 30 Tablets NDC – 43598-944-30 Unit of Use Bottles of 90 Tablets NDC – 43598-944-90 Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].
Protect from moisture and humidity.
📋 Description ▾
11 DESCRIPTION Venlafaxine extended-release tablets are extended-release tablets for oral administration that contain venlafaxine hydrochloride, a structurally novel antidepressant. Venlafaxine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C 17 H 27 NO 2 HCl.
Its molecular weight is 313.9. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline powder with a solubility of freely soluble in water and methanol, soluble in anhydrous ethanol and slightly soluble or practically insoluble in acetone.
Venlafaxine extended-release tablets are formulated as extended-release tablet for once-a-day oral administration. Venlafaxine extended-release tablets is comprised of a matrix system containing. hydrophilic polymers surrounded by an insoluble but permeable coat. After administaration, the soluble components of the coat dissolve and fluid from the gastrointestinal tract enters the tablet through the porous coat, causing the polymers to hydrate and swell.
Drug is released slowly from the dosage form by a process of diffusion and erosion of the polymeric matrix Tablets contain venlafaxine hydrochloride equivalent to 150 mg, or 225 mg venlafaxine. Inactive ingredients consist of ammonium hydroxide, colloidal silicon dioxide, dicalcium phosphate anhydrous, ethyl cellulose, hypromellose, magnesium stearate, medium-chain triglycerides, and oleic acid. structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with venlafaxine extended-release tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for venlafaxine extended-release tablets.
The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking venlafaxine extended-release tablets.
17.1Clinical Worsening and Suicide Risk 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.
17.2Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities.
17.3Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of venlafaxine extended-release tablets and triptans, tricyclic antidepressants, opioids, lithium, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements or other serotonergic agents [ see Warnings and Precautions (5.2) and Drug Interactions (7.10) ].
Patients should be cautioned about the concomitant use of venlafaxine extended-release tablets and NSAID’s, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [ see Warnings and Precautions (5.13) and Drug Interactions (7.11) ].
17.4Alcohol Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.
17.5Allergic Reactions Patients should be advised to notify their physician if the… [Excerpted — this section continues on DailyMed.]
🍼 Nursing Mothers ▾
8.3Nursing Mothers Venlafaxine 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.
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics Steady-state concentrations of venlafaxine and O-desmethylvenlafaxine (ODV) in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. The mean ± SD apparent elimination half-life for venlafaxine and ODV after administration of 75 mg venlafaxine extended-release tablets under fed conditions were 10.7±3.2 hours and 12.5±3.0 hours respectively.
Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption and Distribution Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the only major active metabolite.
On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of 75 mg venlafaxine extended-release tablets under fed conditions resulted in mean ± SD venlafaxine C max of 26.9 ± 13.4 ng/mL and AUC of 1536.3 ± 496.8 ng·hr/mL.
T max was 6.3 ± 2.3 hours. ODV mean ± SD C max , AUC, T max after administration of 75 mg venlafaxine extended-release tablets under fed conditions were 97.9 ± 29.4 ng/mL, 2926.0 ± 746.1 ng·hr/mL, and 11.6 ± 2.9 hours, respectively. Administration of venlafaxine hydrochloride extended-release capsules (150 mg q24 hours) generally resulted in lower C max (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later T max (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (C max 's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV).
When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release form of venlafaxine, the exposure to both venlafaxine and ODV would be similar for the two treatments. Venlafaxine extended-release tablets would, therefore, provide a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the pharmacokinetic parameters AUC, C max , and T max of venlafaxine or its active metabolite, ODV, after administration of venlafaxine extended-release tablets.
Time of administration (AM vs PM) would not affect the pharmacokinetics of venlafaxine and ODV. Equal doses of venlafaxine hydrochloride extended-release tablets are bioequivalent to Effexor XR capsules when administered under fed conditions. Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites.
In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent.
Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. Special Populations Age and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences.
Dosage adjustment based on the age or gende… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV) have no significant affinity for muscarinic cholinergic, H 1 -histaminergic, or α 1 -adrenergic receptors in vitro . Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES
14.1Major Depressive Disorder The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder. A 12-week study utilizing venlafaxine hydrochloride extended-release capsules doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing venlafaxine hydrochloride extended-release capsules doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of venlafaxine hydrochloride extended-release capsules over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item.
In both studies, venlafaxine hydrochloride extended-release capsules were also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing venlafaxine hydrochloride immediate-release tablets in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of venlafaxine hydrochloride immediate-release tablets over placebo.
The mean dose in completers was 350 mg/day. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsules dose or to placebo, for up to 26 weeks of observation for relapse.
Response during the open 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 capsules treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 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 HAM-D-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 immediate-release tablets (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same dose of venlafaxine hydrochloride immediate-release tablets 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 treatment with venlafaxine hydrochloride immediate-release tablets experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
14.2Social Anxiety Disorder (Social Phobia) The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Social A… [Excerpted — this section continues on DailyMed.]
🔒 Drug Abuse and Dependence ▾
9 DRUG ABUSE AND DEPENDENCE
9.1Controlled Substance Venlafaxine extended-release tablets are not a controlled substance.
9.2Abuse While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
9.3Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.
Discontinuation effects have been reported in patients receiving venlafaxine [ see Dosage and Administration (2.4) and Warnings and Precautions (5.5) ].
🔒 Controlled Substance ▾
9.1Controlled Substance Venlafaxine extended-release tablets are not a controlled substance.
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m 2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose.
Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenesis Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay.
Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m 2 basis.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m 2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose.
Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenesis Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay.
Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m 2 basis.
📄 Recent Major Changes ▾
Warning and Precautions (5.2, 5.13) 8/2023
📄 Package Label / Principal Display Panel ▾
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL venla-spl-15030s venla-spl-15090s venla-spl-22530s venla-spl-22590s