VENLAFAXINE: 47,931 Adverse Event Reports & Safety Profile

Venlafaxine extended-release tablets are extended-release tablets for oral administration that contain venlafaxine hydrochloride USP, a structurally novel antidepressant. Venlafaxine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is designated 1-[(1 RS )-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 or almost white powder freely soluble in methanol and water; soluble in anhydrous ethanol and slightly soluble or practically insoluble in acetone. Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Venlafaxine extended-release tablets are formulated as extended-release tablet for once-a-day oral administration. Venlafaxine extended-release tablets use osmotic pressure to deliver venlafaxine hydrochloride at a controlled rate over approximately 24 hours. The system, which resembles a conventional tablet in appearance, comprises an osmotically active core surrounded by a semipermeable membrane. The unitary tablet core is composed of the drug and excipients (including the osmotically active components). There is a precision-laser drilled orifice in the semipermeable membrane on the side of the tablet. In an aqueous environment, such as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing the drug to dissolve and the osmotic components to expand. This expansion pushes the drug out through the orifice. The semipermeable membrane controls the rate at which water permeates into the tablet core, which in turn controls the rate of drug delivery. The controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or gastrointestinal motility. The function of venlafaxine extended-release tablets depends on the existence of an osmotic gradient between the contents of the core and the fluid in the gastrointestinal tract. Since the osmotic gradient remains constant, drug delivery remains essentially constant. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell. Each extended-release tablet contains venlafaxine hydrochloride, USP equivalent to 37.5 mg, 75 mg, 150 mg, or 225 mg venlafaxine. Inactive ingredients consist of cellulose acetate, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, opacode black ink (S-1-277001) (ferrosoferric oxide, propylene glycol and shellac), opadry white 03L580003 (hypromellose, propylene glycol, titanium dioxide and triacetin), polyethylene glycol, povidone. venlafaxine-struct

INDICATIONS AND USAGE Major Depressive Disorder Venlafaxine Hydrochloride Extended-Release Capsules USP are indicated for the treatment of major depressive disorder. The efficacy of Venlafaxine Hydrochloride Extended-Release Capsules USP in the treatment of major depressive disorder was established in 8 and 12 week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials ). 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. The efficacy of Venlafaxine Hydrochloride Tablets USP (immediate release) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4 week controlled trial (see Clinical Trials ). The safety and efficacy of Venlafaxine Hydrochloride Extended-Release Capsules USP in hospitalized depressed patients have not been adequately studied. The efficacy of Venlafaxine Hydrochloride Extended-Release Capsules USP in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Venlafaxine Hydrochloride Tablets USP (immediate release) 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 followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials ). Nevertheless, the physician who elects to use Venlafaxine Hydrochloride Tablets USP/Venlafaxine Hydrochloride Extended-Release Capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Panic Disorder Venlafaxine Hydrochloride

Extended-Release Capsules USP are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes. The efficacy of Venlafaxine Hydrochloride Extended-Release Capsules USP in the treatment of panic disorder was established in two 12 week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Venlafaxine Hydrochloride Extended-Release Capsules USP in prolonging time to relapse in panic disorder among responders following 12 weeks of open-label acute treatment was demonstrated in a placebo-controlled study (see CLINICAL PHARMACOLOGY, Clinical Trials ). Nevertheless, the physician who elects to use Venlafaxine Hydrochloride Extended-Release Capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION Venlafaxine hydrochloride extended-release capsules should be administered in a single dose with food, either in the morning or in the evening at approximately the same time each day [see Clinical Pharmacology (12.3)]. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets (spheroids).

Indication Starting Dose Target Dose

Maximum Dose MDD (2.1) 37.5 to 75 mg/day 75 mg/day 225 mg/day GAD (2.2) 37.5 to 75 mg/day 75 mg/day 225 mg/day SAD (2.3) 75 mg/day 75 mg/day 75 mg/day PD (2.4) 37.5 mg/day 75 mg/day 225 mg/day

• Take once daily with food (2). Capsules should be taken whole; do not divide, crush, chew, or dissolve (2).
• When discontinuing treatment, reduce the dose gradually (2.8, 5.7).
• Renal impairment: reduce the total daily dose by 25% to 50% in patients with renal impairment. Reduce the total daily dose by 50% or more in patients undergoing dialysis or with severe renal impairment (2.6).
• Hepatic impairment: reduce the daily dose by 50% in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment or hepatic cirrhosis, it may be necessary to reduce the dose by more than 50% (2.6).

2.1 Major Depressive Disorder For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more. It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg per day for venlafaxine tablets (immediate-release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg per day (range of 150 to 375 mg per day). Whether or not higher doses of venlafaxine hydrochloride extended- release capsules are needed for more severely depressed patients is unknown; however, the experience with venlafaxine hydrochloride extended-release capsules doses higher than 225 mg per day is very limited.

2.2 Generalized Anxiety Disorder For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

2.3 Social Anxiety Disorder (Social Phobia) The recommended dose is 75 mg per day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.

2.4 Panic Disorder The recommended starting dose is 37.5 mg per day of venlafaxine hydrochloride extended-release capsules for 7 days. Patients not responding to 75 mg per day may benefit from dose increases to a maximum of approximately 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 7 days.

2.5 Switching Patients from Venlafaxine Tablets Depressed patients who are currently being treated at a therapeutic dose with venlafaxine tablets (immediate release) may be switched to venlafaxine hydrochloride extended-release capsules at the nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg venlafaxine hydrochloride extended-release capsules once daily. However, individual dosage adjustments may be necessary.

2.6 Specific Populations Patients with Hepatic Impairment The total daily dose should be reduced by 50% in patients with mild (Child-Pugh = 5 to 6) to moderate (Child-Pugh = 7 to 9) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh = 10 to 15) or hepatic cirrhosis, it may be necessary to reduce the dose by 50% or more <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7)]</span>. Patients with Renal Impairment The total daily dose should be reduced by 25% to 50% in patients with mild (CLcr = 60 to 89 mL/min) or moderate (CLcr = 30 to 59 mL/min) renal impairment. In patients undergoing hemodialysis or with severe renal impairment (CLcr &lt; 30 mL/min), the total daily dose should be reduced by 50% or more. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7)]</span>.

2.7 Maintenance Treatment There is no body of evidence available from controlled studies to indicate how long patients with MDD, GAD, SAD, or PD should be treated with venlafaxine hydrochloride extended-release capsules. It is generally agreed that acute episodes of MDD require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Venlafaxine hydrochloride extended- release capsules/venlafaxine tablets have demonstrated continuation of response in clinical studies up to 52 weeks, at the same dose at which patients responded during the initial treatment <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span>. It is not known whether or not the dose of venlafaxine hydrochloride extended-release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with GAD and SAD, venlafaxine hydrochloride extended-release capsules have been shown to be effective in 6-month clinical studies. The need for continuing medication in patients with GAD and SAD who improve with venlafaxine hydrochloride extended-release capsule treatment should be periodically reassessed. In a clinical study for PD, patients continuing venlafaxine hydrochloride extended-release capsules at the same dose at which they responded during the initial 12 weeks of treatment experienced a statistically significantly longer time to relapse than patients randomized to placebo <span class="opacity-50 text-xs">[see Clinical Studies (14.4)]</span>. The need for continuing medication in patients with PD who improve with venlafaxine hydrochloride extended-release capsule treatment should be periodically reassessed.

2.8 Discontinuing Venlafaxine Hydrochloride Extended-release Capsules A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. In clinical studies with venlafaxine hydrochloride extended-release capsules, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7)]</span>.

2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI (intended to treat psychiatric disorders) and initiation of therapy with venlafaxine hydrochloride extended-release capsules. In addition, at least 7 days should be allowed after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI intended to treat psychiatric disorders <span class="opacity-50 text-xs">[see Contraindications (4.2), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Use of Venlafaxine Hydrochloride Extended-release Capsules with other MAOIs such as Linezolid or Intravenous Methylene Blue Do not start venlafaxine hydrochloride extended-release capsules in a patient who is being treated with linezolid or intravenous methylene blue, because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization should be considered <span class="opacity-50 text-xs">[see Contraindications (4.2)]</span>. In some cases, a patient already receiving venlafaxine hydrochloride extended-release capsule therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine hydrochloride extended-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. Monitor the patient for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with venlafaxine hydrochloride extended-release capsules can be resumed 24 hours after the last dose of linezolid or intravenous methylene blue <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span>. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg concomitantly with venlafaxine hydrochloride extended-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span>.

2.1 Major Depressive Disorder For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more. It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg per day for venlafaxine tablets (immediate-release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg per day (range of 150 to 375 mg per day). Whether or not higher doses of venlafaxine hydrochloride extended- release capsules are needed for more severely depressed patients is unknown; however, the experience with venlafaxine hydrochloride extended-release capsules doses higher than 225 mg per day is very limited.

2.2 Generalized Anxiety Disorder For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

2.3 Social Anxiety Disorder (Social Phobia) The recommended dose is 75 mg per day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.

2.4 Panic Disorder The recommended starting dose is 37.5 mg per day of venlafaxine hydrochloride extended-release capsules for 7 days. Patients not responding to 75 mg per day may benefit from dose increases to a maximum of approximately 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 7 days.

2.5 Switching Patients from Venlafaxine Tablets Depressed patients who are currently being treated at a therapeutic dose with venlafaxine tablets (immediate release) may be switched to venlafaxine hydrochloride extended-release capsules at the nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg venlafaxine hydrochloride extended-release capsules once daily. However, individual dosage adjustments may be necessary.

2.6 Specific Populations Patients with Hepatic Impairment The total daily dose should be reduced by 50% in patients with mild (Child-Pugh = 5 to 6) to moderate (Child-Pugh = 7 to 9) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh = 10 to 15) or hepatic cirrhosis, it may be necessary to reduce the dose by 50% or more <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7)]</span>. Patients with Renal Impairment The total daily dose should be reduced by 25% to 50% in patients with mild (CLcr = 60 to 89 mL/min) or moderate (CLcr = 30 to 59 mL/min) renal impairment. In patients undergoing hemodialysis or with severe renal impairment (CLcr &lt; 30 mL/min), the total daily dose should be reduced by 50% or more. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7)]</span>.

2.7 Maintenance Treatment There is no body of evidence available from controlled studies to indicate how long patients with MDD, GAD, SAD, or PD should be treated with venlafaxine hydrochloride extended-release capsules. It is generally agreed that acute episodes of MDD require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Venlafaxine hydrochloride extended- release capsules/venlafaxine tablets have demonstrated continuation of response in clinical studies up to 52 weeks, at the same dose at which patients responded during the initial treatment <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span>. It is not known whether or not the dose of venlafaxine hydrochloride extended-release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with GAD and SAD, venlafaxine hydrochloride extended-release capsules have been shown to be effective in 6-month clinical studies. The need for continuing medication in patients with GAD and SAD who improve with venlafaxine hydrochloride extended-release capsule treatment should be periodically reassessed. In a clinical study for PD, patients continuing venlafaxine hydrochloride extended-release capsules at the same dose at which they responded during the initial 12 weeks of treatment experienced a statistically significantly longer time to relapse than patients randomized to placebo <span class="opacity-50 text-xs">[see Clinical Studies (14.4)]</span>. The need for continuing medication in patients with PD who improve with venlafaxine hydrochloride extended-release capsule treatment should be periodically reassessed.

2.8 Discontinuing Venlafaxine Hydrochloride Extended-release Capsules A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. In clinical studies with venlafaxine hydrochloride extended-release capsules, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7)]</span>.

2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI (intended to treat psychiatric disorders) and initiation of therapy with venlafaxine hydrochloride extended-release capsules. In addition, at least 7 days should be allowed after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI intended to treat psychiatric disorders <span class="opacity-50 text-xs">[see Contraindications (4.2), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Use of Venlafaxine Hydrochloride Extended-release Capsules with other MAOIs such as Linezolid or Intravenous Methylene Blue Do not start venlafaxine hydrochloride extended-release capsules in a patient who is being treated with linezolid or intravenous methylene blue, because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization should be considered <span class="opacity-50 text-xs">[see Contraindications (4.2)]</span>. In some cases, a patient already receiving venlafaxine hydrochloride extended-release capsule therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine hydrochloride extended-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. Monitor the patient for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with venlafaxine hydrochloride extended-release capsules can be resumed 24 hours after the last dose of linezolid or intravenous methylene blue <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span>. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg concomitantly with venlafaxine hydrochloride extended-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span>.

CONTRAINDICATIONS

4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]</span>.

• Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the venlafaxine hydrochloride extended-release capsules formulation (4.1).
• Do not use with an MAOI or within 14 days of stopping an MAOI.

Allow

7 days after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI, because of the risk of serotonin syndrome (4.2, 5.2, 7.3).

4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]</span>.

4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]</span>.

REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Hypersensitivity [ see Contraindications (4) ]

Suicidal

Thoughts and Behaviors in Adolescents and Young Adults [ see Warnings and Precautions (5.1) ]

Serotonin

Syndrome [ see Warnings and Precautions (5.2) ]

Elevated Blood

Pressure [ see Warnings and Precautions (5.3) ]

Increased

Risk of Bleeding [ see Warnings and Precautions (5.4) ]

Angle Closure

Glaucoma [ see Warnings and Precautions (5.5) ] Activation of Mania/Hypomania [ see Warnings and Precautions (5.6) ]

Discontinuation

Syndrome [ see Warnings and Precautions (5.7) ] Seizure [ see Warnings and Precautions (5.8) ] Hyponatremia [ see Warnings and Precautions (5.9) ] Weight and Height changes in Pediatric Patients [ see Warnings and Precautions (5.10) ]

Appetite

Changes in Pediatric Patients [ see Warnings and Precautions (5.11) ]

Interstitial Lung

Disease and Eosinophilic Pneumonia [ see Warnings and Precautions (5.12) ]

Sexual

Dysfunction [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, impotence (men), and libido decreased (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Marlex Pharmaceuticals at 1-888-582-1953 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience 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 studies of another drug and may not reflect the rates observed in clinical practice.

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database in Venlafaxine hydrochloride extended-release capsules treated patients in MDD, GAD, SAD, and PD (incidence ≥5% and at least twice the rate of placebo) were: nausea (30.0%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%) and decreased libido (5.1%).

Adverse Reactions

Reported as Reasons for Discontinuation of Treatment Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the 3,558 patients who received Venlafaxine hydrochloride extended-release capsules (37.5-225 mg) discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated patients in those studies. The most common adverse reactions leading to discontinuation in ≥1% of the Venlafaxine hydrochloride extended-release capsules treated patients in the short-term studies (up to 12 weeks) across indications are shown in Table 7.

Table

7: Incidence (%) of Patients Reporting Adverse Reactions Leading to Discontinuation in Placebo-controlled Clinical Studies (up to 12 Weeks Duration)

Body System Adverse Reaction

Venlafaxine hydrochloride extended-release capsules n = 3,558 Placebo n = 2,197 Body as a whole - - Asthenia 1.7

0.5 Headache 1.5

0.8 Digestive system - - Nausea 4.3

0.4 Nervous system - - Dizziness 2.2

0.8 Insomnia 2.1

0.6 Somnolence 1.7

0.3 Skin and appendages 1.5

0.6 Sweating 1.0

0.2 Common Adverse Reactions in Placebo-controlled Studies The number of patients receiving multiple doses of Venlafaxine hydrochloride extended-release capsules during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine hydrochloride tablets only) and outpatient studies, fixed-dose, and titration studies.

Table

8: Patients Receiving Venlafaxine Hydrochloride Extended-release Capsulesin Premarketing Clinical Studies a In addition, in the premarketing assessment of venlafaxine hydrochloride tablets, multiple doses were administered to 2,897 patients in studies for MDD.

Indication

Venlafaxine hydrochloride extended-release capsules MDD 705 a GAD 1,381 SAD 819 PD 1,314 The incidences of common adverse reactions (those that occurred in ≥2% of venlafaxine hydrochloride extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride extended-release capsules treated patients in short-term, placebo-controlled, fixed-and flexible-dose clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9. The adverse reaction profile did not differ substantially between the different patient populations.

Table

9: Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (≥2% and >placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications a Percentages based on the number of men (Venlafaxine hydrochloride extended-release capsules, n = 1,440; placebo, n = 923) b Percentages based on the number of women (Venlafaxine hydrochloride extended-release capsules, n = 2,118; placebo, n = 1,274)

Body System Adverse Reaction

Venlafaxine hydrochloride extended-release capsules n = 3,558 Placebo n = 2,197 Body as a whole - - Asthenia 12.6

7.8 Cardiovascular system - - Hypertension 3.4

2.6 Palpitation 2.2

2.0 Vasodilatation 3.7

1.9 Digestive system - - Anorexia 9.8

2.6 Constipation 9.3

3.4 Diarrhea 7.7

7.2 Dry mouth 14.8

5.3 Nausea 30.0

11.8 Vomiting 4.3

2.7 Nervous system - - Abnormal dreams 2.9

1.4 Dizziness 15.8

9.5 Insomnia 17.8

9.5 Libido decreased 5.1

1.6 Nervousness 7.1

5.0 Paresthesia 2.4

1.4 Somnolence 15.3

7.5 Tremor 4.7

1.6 Respiratory system - - Yawn 3.7

0.2 Skin and appendages - - Sweating (including night sweats) 11.4

2.9 Special senses - - Abnormal vision 4.2

1.6 Urogenital system - - Abnormal ejaculation/orgasm (men)a 9.9

0.5 Anorgasmia (men)a 3.6

0.1 Anorgasmia (women)b 2.0

0.2 Impotence (men)a 5.3

1.0 Other Adverse Reactions Observed in Clinical Studies Body as a Whole – Photosensitivity reaction, chills Cardiovascular System – Postural hypotension, syncope, hypotension, tachycardia Digestive System – Gastrointestinal hemorrhage [ see Warnings and Precautions (5.4) ], bruxism Hemic/Lymphatic System – Ecchymosis [ see Warnings and Precautions (5.4) ] Metabolic/Nutritional – Hypercholesterolemia, weight gain [ see Warnings and Precautions (5.10) ], weight loss [ see Warnings and Precautions (5.10) ]

Nervous

System – Seizures [ see Warnings and Precautions (5.8) ], manic reaction [ see Warnings and Precautions (5.6) ], agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy Skin and Appendages – Urticaria, pruritus, rash, alopecia Special Senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion Urogenital System – Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia)

Vital Sign

Changes In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with Venlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SDBP of ≥15 mm Hg along with a blood pressure ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Venlafaxine hydrochloride extended-release capsules groups experienced an increase in SSBP of ≥20 mm Hg with a blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups.

Table

10: Final On-therapy Mean Changes from Baseline in Supine Systolic (SSBP) and Diastolic (SDBP)

Blood

Pressure (mm Hg) in Placebo-controlled Studies - Venlafaxine HCl ER Capsules Placebo Indication (Duration) ≤75 mg per day >75 mg per day - - SSBP SDBP SSBP SDBP SSBP SDBP MDD - - - - - - (8-12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.10 GAD - - - - - - (8 weeks) -0.28 0.02 2.40 1.68 -1.26 -0.92 (6 months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 SAD - - - - - - (12 weeks) -0.29 -1.26 1.18 1.34 -1.96 -1.22 (6 months) -0.98 -0.49 2.51 1.96 -1.84 -0.65 PD - - - - - - (10-12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99 Venlafaxine hydrochloride extended-release capsules treatment was associated with sustained hypertension (defined as Supine Diastolic Blood Pressure [SDBP] ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient number of patients received mean doses of Venlafaxine hydrochloride extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

Table

11: Sustained Elevations in SDBP in Venlafaxine hydrochloride extended-release capsules Premarketing Studies a Maximum recommended dosage for venlafaxine hydrochloride extended-release capsules is 225 mg once daily.

Indication Dose

Range (mg per day) Incidence (%) MDD 75-375 a 19/705 (3) GAD 37.5-225 5/1011 (0.3) SAD 75-225 5/771 (0.6) PD 75-225 9/973 (0.9) Venlafaxine hydrochloride extended-release capsules was associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 12) [ see Warnings and Precautions (5.3 , 5.4) ].

Table

12: Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine hydrochloride extended-release capsulesPremarketing Placebo-controlled Studies (up to 12 Weeks Duration) Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD - - (12 weeks) 2 1 GAD - - (8 weeks) 2 < 1 SAD - - (12 weeks) 3 1 PD - - (12 weeks) 1 < 1 Laboratory Changes Serum Cholesterol Venlafaxine hydrochloride extended-release capsules were associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13).

Table

13: Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine hydrochloride extended-release capsulesPremarketing Studies Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD - - (12 weeks) +1.5 -7.4 GAD - - (8 weeks) +1.0 -4.9 (6 months) +2.3 -7.7 SAD - - (12 weeks) +7.9 -2.9 (6 months) +5.6 -4.2 PD - - (12 weeks) +5.8 -3.7 Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with venlafaxine hydrochloride tablets (immediate-release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsules was associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14).

Table

14: Mean Final On-therapy Increases in Triglyceride Concentrations (mg/dL) in Venlafaxine hydrochloride extended-release capsules Premarketing Studies Indication (Duration) Venlafaxine HCl ER Capsules Placebo SAD (12 weeks) 8.2

0.4 SAD (6 months) 11.8

1.8 PD (12 weeks) 5.9

0.9 PD (6 months) 9.3 0.3

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Venlafaxine hydrochloride extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole – Anaphylaxis, angioedema Cardiovascular System – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy Digestive System – Pancreatitis Hemic/Lymphatic System – Mucous membrane bleeding [ see Warnings and Precautions (5.4 ) ], blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional – Hyponatremia [ see Warnings and Precautions (5.9) ], Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [ see Warnings and Precautions (5.9) ], abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal – Rhabdomyolysis Nervous System – Neuroleptic Malignant Syndrome (NMS) [ see Warnings and Precautions (5.2) ], serotonergic syndrome [ see Warnings and Precautions (5.2) ], delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia Respiratory Thoracic and Mediastinal Disorders –Anosmia, Dyspnea, hyposmia, interstitial lung disease pulmonary eosinophilia [ see Warnings and Precautions (5.12) ] Skin and Appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special Senses – Angle-closure glaucoma [ see Warnings and Precautions (5.5) ]

6.1 Clinical Studies Experience 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 studies of another drug and may not reflect the rates observed in clinical practice.

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database in Venlafaxine hydrochloride extended-release capsules treated patients in MDD, GAD, SAD, and PD (incidence ≥5% and at least twice the rate of placebo) were: nausea (30.0%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%) and decreased libido (5.1%).

Adverse Reactions

Reported as Reasons for Discontinuation of Treatment Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the 3,558 patients who received Venlafaxine hydrochloride extended-release capsules (37.5-225 mg) discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated patients in those studies. The most common adverse reactions leading to discontinuation in ≥1% of the Venlafaxine hydrochloride extended-release capsules treated patients in the short-term studies (up to 12 weeks) across indications are shown in Table 7.

Table

7: Incidence (%) of Patients Reporting Adverse Reactions Leading to Discontinuation in Placebo-controlled Clinical Studies (up to 12 Weeks Duration)

Body System Adverse Reaction

Venlafaxine hydrochloride extended-release capsules n = 3,558 Placebo n = 2,197 Body as a whole - - Asthenia 1.7

0.5 Headache 1.5

0.8 Digestive system - - Nausea 4.3

0.4 Nervous system - - Dizziness 2.2

0.8 Insomnia 2.1

0.6 Somnolence 1.7

0.3 Skin and appendages 1.5

0.6 Sweating 1.0

0.2 Common Adverse Reactions in Placebo-controlled Studies The number of patients receiving multiple doses of Venlafaxine hydrochloride extended-release capsules during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine hydrochloride tablets only) and outpatient studies, fixed-dose, and titration studies.

Table

8: Patients Receiving Venlafaxine Hydrochloride Extended-release Capsulesin Premarketing Clinical Studies a In addition, in the premarketing assessment of venlafaxine hydrochloride tablets, multiple doses were administered to 2,897 patients in studies for MDD.

Indication

Venlafaxine hydrochloride extended-release capsules MDD 705 a GAD 1,381 SAD 819 PD 1,314 The incidences of common adverse reactions (those that occurred in ≥2% of venlafaxine hydrochloride extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride extended-release capsules treated patients in short-term, placebo-controlled, fixed-and flexible-dose clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9. The adverse reaction profile did not differ substantially between the different patient populations.

Table

9: Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (≥2% and >placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications a Percentages based on the number of men (Venlafaxine hydrochloride extended-release capsules, n = 1,440; placebo, n = 923) b Percentages based on the number of women (Venlafaxine hydrochloride extended-release capsules, n = 2,118; placebo, n = 1,274)

Body System Adverse Reaction

Venlafaxine hydrochloride extended-release capsules n = 3,558 Placebo n = 2,197 Body as a whole - - Asthenia 12.6

7.8 Cardiovascular system - - Hypertension 3.4

2.6 Palpitation 2.2

2.0 Vasodilatation 3.7

1.9 Digestive system - - Anorexia 9.8

2.6 Constipation 9.3

3.4 Diarrhea 7.7

7.2 Dry mouth 14.8

5.3 Nausea 30.0

11.8 Vomiting 4.3

2.7 Nervous system - - Abnormal dreams 2.9

1.4 Dizziness 15.8

9.5 Insomnia 17.8

9.5 Libido decreased 5.1

1.6 Nervousness 7.1

5.0 Paresthesia 2.4

1.4 Somnolence 15.3

7.5 Tremor 4.7

1.6 Respiratory system - - Yawn 3.7

0.2 Skin and appendages - - Sweating (including night sweats) 11.4

2.9 Special senses - - Abnormal vision 4.2

1.6 Urogenital system - - Abnormal ejaculation/orgasm (men)a 9.9

0.5 Anorgasmia (men)a 3.6

0.1 Anorgasmia (women)b 2.0

0.2 Impotence (men)a 5.3

1.0 Other Adverse Reactions Observed in Clinical Studies Body as a Whole – Photosensitivity reaction, chills Cardiovascular System – Postural hypotension, syncope, hypotension, tachycardia Digestive System – Gastrointestinal hemorrhage [ see Warnings and Precautions (5.4) ], bruxism Hemic/Lymphatic System – Ecchymosis [ see Warnings and Precautions (5.4) ] Metabolic/Nutritional – Hypercholesterolemia, weight gain [ see Warnings and Precautions (5.10) ], weight loss [ see Warnings and Precautions (5.10) ]

Nervous

System – Seizures [ see Warnings and Precautions (5.8) ], manic reaction [ see Warnings and Precautions (5.6) ], agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy Skin and Appendages – Urticaria, pruritus, rash, alopecia Special Senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion Urogenital System – Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia)

Vital Sign

Changes In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with Venlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SDBP of ≥15 mm Hg along with a blood pressure ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Venlafaxine hydrochloride extended-release capsules groups experienced an increase in SSBP of ≥20 mm Hg with a blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups.

Table

10: Final On-therapy Mean Changes from Baseline in Supine Systolic (SSBP) and Diastolic (SDBP)

Blood

Pressure (mm Hg) in Placebo-controlled Studies - Venlafaxine HCl ER Capsules Placebo Indication (Duration) ≤75 mg per day >75 mg per day - - SSBP SDBP SSBP SDBP SSBP SDBP MDD - - - - - - (8-12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.10 GAD - - - - - - (8 weeks) -0.28 0.02 2.40 1.68 -1.26 -0.92 (6 months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 SAD - - - - - - (12 weeks) -0.29 -1.26 1.18 1.34 -1.96 -1.22 (6 months) -0.98 -0.49 2.51 1.96 -1.84 -0.65 PD - - - - - - (10-12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99 Venlafaxine hydrochloride extended-release capsules treatment was associated with sustained hypertension (defined as Supine Diastolic Blood Pressure [SDBP] ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient number of patients received mean doses of Venlafaxine hydrochloride extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

Table

11: Sustained Elevations in SDBP in Venlafaxine hydrochloride extended-release capsules Premarketing Studies a Maximum recommended dosage for venlafaxine hydrochloride extended-release capsules is 225 mg once daily.

Indication Dose

Range (mg per day) Incidence (%) MDD 75-375 a 19/705 (3) GAD 37.5-225 5/1011 (0.3) SAD 75-225 5/771 (0.6) PD 75-225 9/973 (0.9) Venlafaxine hydrochloride extended-release capsules was associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 12) [ see Warnings and Precautions (5.3 , 5.4) ].

Table

12: Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine hydrochloride extended-release capsulesPremarketing Placebo-controlled Studies (up to 12 Weeks Duration) Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD - - (12 weeks) 2 1 GAD - - (8 weeks) 2 < 1 SAD - - (12 weeks) 3 1 PD - - (12 weeks) 1 < 1 Laboratory Changes Serum Cholesterol Venlafaxine hydrochloride extended-release capsules were associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13).

Table

13: Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine hydrochloride extended-release capsulesPremarketing Studies Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD - - (12 weeks) +1.5 -7.4 GAD - - (8 weeks) +1.0 -4.9 (6 months) +2.3 -7.7 SAD - - (12 weeks) +7.9 -2.9 (6 months) +5.6 -4.2 PD - - (12 weeks) +5.8 -3.7 Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with venlafaxine hydrochloride tablets (immediate-release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsules was associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14).

Table

14: Mean Final On-therapy Increases in Triglyceride Concentrations (mg/dL) in Venlafaxine hydrochloride extended-release capsules Premarketing Studies Indication (Duration) Venlafaxine HCl ER Capsules Placebo SAD (12 weeks) 8.2

0.4 SAD (6 months) 11.8

1.8 PD (12 weeks) 5.9

0.9 PD (6 months) 9.3 0.3

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Venlafaxine hydrochloride extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole – Anaphylaxis, angioedema Cardiovascular System – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy Digestive System – Pancreatitis Hemic/Lymphatic System – Mucous membrane bleeding [ see Warnings and Precautions (5.4 ) ], blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional – Hyponatremia [ see Warnings and Precautions (5.9) ], Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [ see Warnings and Precautions (5.9) ], abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal – Rhabdomyolysis Nervous System – Neuroleptic Malignant Syndrome (NMS) [ see Warnings and Precautions (5.2) ], serotonergic syndrome [ see Warnings and Precautions (5.2) ], delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia Respiratory Thoracic and Mediastinal Disorders –Anosmia, Dyspnea, hyposmia, interstitial lung disease pulmonary eosinophilia [ see Warnings and Precautions (5.12) ] Skin and Appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special Senses – Angle-closure glaucoma [ see Warnings and Precautions (5.5) ]

AND PRECAUTIONS .

Serotonin

Syndrome : Increased risk when co-administered with other serotonergic agents but also when taken alone. If it occurs, discontinue Venlafaxine hydrochloride extended-release capsules and serotonergic agents and initiate supportive treatment ( 4 , 5.2 , 7.1 ).

Elevated Blood

Pressure : Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3 ).

Increased

Risk of Bleeding : Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk ( 5.4 ). Angle-Closure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.5 ). Activation of Mania /or Hypomania : Screen patients for bipolar disorder ( 5.6 ).

Discontinuation

Syndrome: Taper dose and monitor for discontinuation symptoms ( 5.7 ). Seizures : Can occur. Use cautiously in patients with seizure disorder ( 5.8 ). Hyponatremia : Can occur in association with SIADH ( 5.9 ).

Interstitial Lung

Disease and Eosinophilic Pneumonia : Can occur ( 5.12 ).

Sexual

Dysfunction : Venlafaxine hydrochloride extended-release capsules may cause symptoms of sexual dysfunction ( 5.13 ).

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 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.

Table

1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric * and Adult 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 * Venlafaxine hydrochloride extended-release capsules is not approved in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Venlafaxine hydrochloride extended-release capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Venlafaxine hydrochloride extended-release capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination); seizures and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Venlafaxine hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate Venlafaxine hydrochloride extended-release capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Venlafaxine hydrochloride extended-release capsules, discontinue Venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Monitor all patients taking Venlafaxine hydrochloride extended-release capsules for the emergence of serotonin syndrome. Discontinue treatment with Venlafaxine hydrochloride extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Venlafaxine hydrochloride extended-release capsules with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Elevated Blood Pressure In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Monitor blood pressure before initiating treatment with Venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with Venlafaxine hydrochloride extended-release capsules. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with Venlafaxine hydrochloride extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure. Across all clinical studies with venlafaxine hydrochloride tablets, 1.4% of patients in the Venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups [ see in Adverse Reactions (6.1) ]. Treatment with venlafaxine hydrochloride extended-release capsules was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsule over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Venlafaxine hydrochloride extended-release capsules, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>. Inform patients about the increased risk of bleeding associated with the concomitant use of Venlafaxine hydrochloride extended-release capsules and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine hydrochloride extended-release capsules.

5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Venlafaxine hydrochloride extended-release capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Venlafaxine hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with Venlafaxine hydrochloride extended-release capsules or another antidepressant may precipitate a mixed/maniac episode. Mania or hypomania was reported in Venlafaxine hydrochloride extended-release capsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Venlafaxine hydrochloride extended-release capsules, screen for any personal or family history of bipolar disorder, mania, or hypomania.

Table

2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine hydrochloride extended-release capsulesTreated Patients in the Premarketing Studies Indication Venlafaxine hydrochloride extended-release capsules Placebo MDD 0.3

0.0 GAD 0.0

0.2 SAD 0.2

0.0 PD 0.1 0.0

5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in Venlafaxine hydrochloride extended-release capsules dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of Venlafaxine hydrochloride extended-release capsules. During marketing of Venlafaxine hydrochloride extended-release capsules, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures. Patients should be monitored for these symptoms when discontinuing treatment with Venlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months <span class="opacity-50 text-xs">[see Dosage and Administration (2.10)]</span>.

5.8 Seizures Cases of seizure have been reported with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules has not been systematically evaluated in patients with seizure disorder. Venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including Venlafaxine hydrochloride extended-release capsules. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]</span> . Consider discontinuation of Venlafaxine hydrochloride extended-release capsules in patients with symptomatic hyponatremia, and institute appropriate medical intervention. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.10 Weight and Height Changes in Pediatric Patients Weight Changes The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5% or more) in the placebo-controlled pediatric studies in MDD, GAD, and SAD are shown in Tables 3 and 4.

Table

3: Average Change in Body Weight (kg)

From

Beginning of Treatment in Pediatric Patients a in Double-blind, Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n=333) +0.77 (n=333) SAD (16 weeks) -0.75 (n=137) +0.76 (n=148)

Table

4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p < 0.001 versus placebo Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) SAD (16 weeks) 47 b (n = 137) 14 (n = 148) Weight loss was not limited to patients with anorexia [ see Warnings and Precautions (5.11) ]. The risks associated with longer term Venlafaxine hydrochloride extended-release capsules use were assessed in an open-label MDD study of children and adolescents who received Venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents in the study had increases in weight that were less than expected, based on data from age-and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [ Use in Specific Populations (8.4) ] .

Height Changes Table

5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were most notable in patients younger than 12 years old.

Table

5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p =

0.041 Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 b (n = 122 1.0 (n = 132) SAD (16 weeks) 1.0 (n = 109) 1.0 (n = 112) In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected, based on data from age-and sex-matched peers. The difference between observed and expected growth rates was larger for children (&lt;12 years old) than for adolescents (≥12 years old) [ see Use in Specific Populations (8.4) ] .

5.11 Appetite Changes in Pediatric Patients Decreased appetite (reported as anorexia) was more commonly observed in Venlafaxine hydrochloride extended-release capsules treated patients versus placebo-treated patients in the premarketing evaluation of Venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

Table

6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a The discontinuation rates for weight loss were 0.7% for patients receiving either Venlafaxine hydrochloride extended-release capsules or placebo. b Venlafaxine hydrochloride extended-release capsules is not approved for use in pediatric patients. - Venlafaxine hydrochloride extended-release capsules Placebo (Duration)

Incidence Discontinuation Incidence

Discontinuation MDD and GAD (pooled, 8 weeks) 10 0.0 3 - SAD (16 weeks) 22 0.7 3 0.0

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in venlafaxine hydrochloride extended-release capsules-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-release should be considered.

5.13 Sexual Dysfunction Use of SNRIs, including Venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of Venlafaxine hydrochloride extended-release capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 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.

Table

1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric * and Adult 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 * Venlafaxine hydrochloride extended-release capsules is not approved in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Venlafaxine hydrochloride extended-release capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Venlafaxine hydrochloride extended-release capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination); seizures and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Venlafaxine hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate Venlafaxine hydrochloride extended-release capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Venlafaxine hydrochloride extended-release capsules, discontinue Venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Monitor all patients taking Venlafaxine hydrochloride extended-release capsules for the emergence of serotonin syndrome. Discontinue treatment with Venlafaxine hydrochloride extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Venlafaxine hydrochloride extended-release capsules with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Elevated Blood Pressure In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Monitor blood pressure before initiating treatment with Venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with Venlafaxine hydrochloride extended-release capsules. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with Venlafaxine hydrochloride extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure. Across all clinical studies with venlafaxine hydrochloride tablets, 1.4% of patients in the Venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups [ see in Adverse Reactions (6.1) ]. Treatment with venlafaxine hydrochloride extended-release capsules was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsule over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Venlafaxine hydrochloride extended-release capsules, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>. Inform patients about the increased risk of bleeding associated with the concomitant use of Venlafaxine hydrochloride extended-release capsules and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine hydrochloride extended-release capsules.

5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Venlafaxine hydrochloride extended-release capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Venlafaxine hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with Venlafaxine hydrochloride extended-release capsules or another antidepressant may precipitate a mixed/maniac episode. Mania or hypomania was reported in Venlafaxine hydrochloride extended-release capsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Venlafaxine hydrochloride extended-release capsules, screen for any personal or family history of bipolar disorder, mania, or hypomania.

Table

2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine hydrochloride extended-release capsulesTreated Patients in the Premarketing Studies Indication Venlafaxine hydrochloride extended-release capsules Placebo MDD 0.3

0.0 GAD 0.0

0.2 SAD 0.2

0.0 PD 0.1 0.0

5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in Venlafaxine hydrochloride extended-release capsules dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of Venlafaxine hydrochloride extended-release capsules. During marketing of Venlafaxine hydrochloride extended-release capsules, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures. Patients should be monitored for these symptoms when discontinuing treatment with Venlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months <span class="opacity-50 text-xs">[see Dosage and Administration (2.10)]</span>.

5.8 Seizures Cases of seizure have been reported with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules has not been systematically evaluated in patients with seizure disorder. Venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including Venlafaxine hydrochloride extended-release capsules. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]</span> . Consider discontinuation of Venlafaxine hydrochloride extended-release capsules in patients with symptomatic hyponatremia, and institute appropriate medical intervention. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.10 Weight and Height Changes in Pediatric Patients Weight Changes The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5% or more) in the placebo-controlled pediatric studies in MDD, GAD, and SAD are shown in Tables 3 and 4.

Table

3: Average Change in Body Weight (kg)

From

Beginning of Treatment in Pediatric Patients a in Double-blind, Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n=333) +0.77 (n=333) SAD (16 weeks) -0.75 (n=137) +0.76 (n=148)

Table

4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p < 0.001 versus placebo Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) SAD (16 weeks) 47 b (n = 137) 14 (n = 148) Weight loss was not limited to patients with anorexia [ see Warnings and Precautions (5.11) ]. The risks associated with longer term Venlafaxine hydrochloride extended-release capsules use were assessed in an open-label MDD study of children and adolescents who received Venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents in the study had increases in weight that were less than expected, based on data from age-and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [ Use in Specific Populations (8.4) ] .

Height Changes Table

5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were most notable in patients younger than 12 years old.

Table

5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p =

0.041 Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 b (n = 122 1.0 (n = 132) SAD (16 weeks) 1.0 (n = 109) 1.0 (n = 112) In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected, based on data from age-and sex-matched peers. The difference between observed and expected growth rates was larger for children (&lt;12 years old) than for adolescents (≥12 years old) [ see Use in Specific Populations (8.4) ] .

5.11 Appetite Changes in Pediatric Patients Decreased appetite (reported as anorexia) was more commonly observed in Venlafaxine hydrochloride extended-release capsules treated patients versus placebo-treated patients in the premarketing evaluation of Venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

Table

6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a The discontinuation rates for weight loss were 0.7% for patients receiving either Venlafaxine hydrochloride extended-release capsules or placebo. b Venlafaxine hydrochloride extended-release capsules is not approved for use in pediatric patients. - Venlafaxine hydrochloride extended-release capsules Placebo (Duration)

Incidence Discontinuation Incidence

Discontinuation MDD and GAD (pooled, 8 weeks) 10 0.0 3 - SAD (16 weeks) 22 0.7 3 0.0

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in venlafaxine hydrochloride extended-release capsules-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-release should be considered.

5.13 Sexual Dysfunction Use of SNRIs, including Venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of Venlafaxine hydrochloride extended-release capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

PRECAUTIONS General Discontinuation of Treatment With Venlafaxine Hydrochloride Extended-Release Capsules Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with venlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION ). Insomnia and Nervousness Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine hydrochloride extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder and panic disorder studies as shown in Table 5 .

Table

4: Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder and Panic Disorder Trials Major Depressive Disorder Panic Disorder Venlafaxine Hydrochloride Extended-Release Capsules Placebo Venlafaxine Hydrochloride Extended-Release Capsules Placebo Symptom n = 357 n = 285 n = 1001 n = 662 Insomnia 17% 11% 17% 9% Nervousness 10% 5% 4% 6% Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with venlafaxine hydrochloride extended-release capsules in major depressive disorder studies. In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with venlafaxine hydrochloride extended-release capsules up to 12 weeks. Changes in Weight Adult Patients A loss of 5% or more of body weight occurred in 7% of venlafaxine hydrochloride extended-release capsule-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with venlafaxine hydrochloride extended-release capsules was 0.1% in major depressive disorder studies. In placebo-controlled panic disorder trials, 3% of the venlafaxine hydrochloride extended-release capsule-treated and 2% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving venlafaxine hydrochloride extended-release capsules in panic disorder studies discontinued for weight loss. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products.

Pediatric Patients

Weight loss has been observed in pediatric patients (ages 6 to 17) receiving venlafaxine hydrochloride extended-release capsules. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials, for major depressive disorder (MDD), venlafaxine hydrochloride extended-release capsule-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with venlafaxine hydrochloride extended-release capsules than with placebo experienced a weight loss of at least 3.5% in the MDD study (18% of venlafaxine hydrochloride extended-release capsule-treated patients vs. 3.6% of placebo-treated patients; p < 0.001) (see PRECAUTIONS , General , Changes in Appetite ). The risks associated with longer-term venlafaxine hydrochloride extended-release capsule use were assessed in an open-label MDD study of children and adolescents who received venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (< 12 years old) than for adolescents (≥ 12 years old). Changes in Height Pediatric Patients During the eight-week placebo-controlled MDD studies, venlafaxine hydrochloride extended-release capsule-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (< 12 years old) than for adolescents (≥ 12 years old). Changes in Appetite Adult Patients Treatment-emergent anorexia was more commonly reported for venlafaxine hydrochloride extended-release capsule-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with venlafaxine hydrochloride extended-release capsules was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for venlafaxine hydrochloride extended-release capsule-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving venlafaxine hydrochloride extended-release capsules for up to 12 weeks in panic disorder studies.

Pediatric Patients

Decreased appetite has been observed in pediatric patients receiving venlafaxine hydrochloride extended-release capsules. In the placebo-controlled trials for MDD, 10% of patients aged 6 to 17 treated with venlafaxine hydrochloride extended-release capsules for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving venlafaxine hydrochloride extended-release capsules discontinued for anorexia or weight loss. Activation of Mania/Hypomania During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of venlafaxine hydrochloride extended-release capsule-treated patients and no placebo patients. In premarketing panic disorder studies, 0.1% of venlafaxine hydrochloride extended-release capsules-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with venlafaxine hydrochloride tablets (immediate release), mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with no placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, venlafaxine hydrochloride extended-release capsules should be used cautiously in patients with a history of mania.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS , Geriatric Use ). Discontinuation of venlafaxine hydrochloride extended-release capsules should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Seizures

During premarketing experience, no seizures occurred among 705 venlafaxine hydrochloride extended-release capsule-treated patients in the major depressive disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 venlafaxine hydrochloride extended-release capsule-treated patients. In all premarketing major depressive disorder trials with venlafaxine hydrochloride tablets (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Venlafaxine hydrochloride extended-release capsules, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.

Abnormal

Bleeding SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, 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. Patients should be cautioned about the risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, or other drugs that affect coagulation.

Serum Cholesterol Elevation

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS , Laboratory Changes ). Measurement of serum cholesterol levels should be considered during long-term treatment.

Interstitial Lung

Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. Use in Patients With Concomitant Illness Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine hydrochloride extended-release capsules to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received venlafaxine hydrochloride extended-release capsules and 220 patients who received placebo in 8 to 12 week double-blind, placebo-controlled trials in major depressive disorder, and for 661 patients who received venlafaxine hydrochloride extended-release capsules and 395 patients who received placebo in three 10 to 12 week double-blind, placebo-controlled trials in panic disorder. The mean change from baseline in corrected QT interval (QT c ) for venlafaxine hydrochloride extended-release capsule-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine hydrochloride extended-release capsules and decrease of 1.9 msec for placebo). The mean change from baseline in QT c interval for venlafaxine hydrochloride extended-release capsule-treated patients in the panic disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for venlafaxine hydrochloride extended-release capsules and decrease of 0.7 msec for placebo). In these same trials, the mean change from baseline in heart rate for venlafaxine hydrochloride extended-release capsule-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine hydrochloride extended-release capsules and 1 beat per minute for placebo). The mean change from baseline in heart rate for venlafaxine hydrochloride extended-release capsule-treated patients in the panic disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for venlafaxine hydrochloride extended-release capsules and a mean decrease of less than 1 beat per minute for placebo). In a flexible-dose study, with venlafaxine hydrochloride tablet (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, venlafaxine hydrochloride tablet-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction). Evaluation of the electrocardiograms for 769 patients who received venlafaxine hydrochloride tablets (immediate release) in 4 to 6 week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION ). Venlafaxine hydrochloride extended-release capsules, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with venlafaxine hydrochloride extended-release capsules 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 hydrochloride extended-release capsules. 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 hydrochloride extended-release capsules.

Clinical

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.

Interference 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.

Concomitant 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 hydrochloride extended-release capsules and triptans, tramadol, tryptophan supplements or other serotonergic agents (see CONTRAINDICATIONS and WARNINGS , Serotonin Syndrome and PRECAUTIONS , Drug Interactions , CNS-Active Drugs , Serotonergic Drugs ). Patients should be advised that taking venlafaxine hydrochloride extended-release capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Preexisting glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Patients should be cautioned about the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, 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 PRECAUTIONS , Abnormal Bleeding ).

Alcohol

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.

Allergic Reactions

Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing

Patients should be advised to notify their physician if they are breast-feeding an infant.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug

Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol 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.

Cimetidine

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 preexisting 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.

Diazepam

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.

Haloperidol

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 C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged. The mechanism explaining this finding is unknown.

Lithium

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).

Drugs Highly

Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride extended-release capsules to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Drugs That Interfere With

Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine hydrochloride extended-release capsules are initiated or discontinued.

Drugs That Inhibit

Cytochrome P450 Isoenzymes CYP2D6 Inhibitors In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see CLINICAL PHARMACOLOGY , Metabolism and Excretion ). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desmethylvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine C max increased by 26% in EM subjects and 48% in PM subjects. C max values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs (range in PMs -4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

Drugs

Metabolized by Cytochrome P450 Isoenzymes CYP2D6 In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max , and C min increased by about 35% in the presence of venlafaxine.

The

2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Metoprolol - Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with coadministration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving venlafaxine hydrochloride extended-release capsules have regular monitoring of blood pressure (see WARNINGS ). Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4 Venlafaxine did not inhibit CYP3A4 in vitro . This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2 Venlafaxine did not inhibit CYP1A2 in vitro . This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9 Venlafaxine did not inhibit CYP2C9 in vitro . In vivo , venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19 Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION . CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required (see CONTRAINDICATIONS and WARNINGS , Serotonin Syndrome ).

Serotonergic Drugs

See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of venlafaxine hydrochloride extended-release capsules with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS , Serotonin Syndrome ). Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine hydrochloride extended-release capsules treatment.

Postmarketing Spontaneous Drug Interaction Reports

See ADVERSE REACTIONS , Postmarketing Reports . Carcinogenesis, 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 of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m 2 basis. However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day.

Pregnancy Teratogenic Effects Pregnancy

Category C 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.

Nonteratogenic 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 PRECAUTIONS , Drug Interactions , CNS-Active Drugs ). When treating a pregnant woman with venlafaxine hydrochloride extended-release capsules during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION ). Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown.

Nursing 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 hydrochloride extended-release capsules, 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

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS , Clinical Worsening and Suicide Risk ). Two placebo-controlled trials in 766 pediatric patients with MDD 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 hydrochloride extended-release capsules in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsules’ impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height (see PRECAUTIONS , General , Changes in Height and Changes in Weight ). Should the decision be made to treat a pediatric patient with venlafaxine hydrochloride extended-release capsules, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of venlafaxine hydrochloride extended-release capsule 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 , Sustained Hypertension and PRECAUTIONS , General , Serum Cholesterol Elevation ).

Geriatric Use Approximately

4% (14/357) and 2% (16/1001) of venlafaxine hydrochloride extended-release capsule-treated patients in placebo-controlled premarketing major depressive disorder and panic disorder trials, respectively, were 65 years of age or over.

Of

2,897 venlafaxine hydrochloride tablet-treated (immediate release) patients 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 event (see PRECAUTIONS , Hyponatremia ). The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY ). 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 ).

Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or 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.

Cimetidine

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, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is 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.

Diazepam

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.

Haloperidol

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 C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged. The mechanism explaining this finding is unknown.

Lithium

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. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs , below).

Drugs Highly

Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine hydrochloride is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O–desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine C max increased by 26% in EM subjects and 48% in PM subjects. C max values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems.

Drugs

Metabolized by Cytochrome P450 Isoenzymes CYP2D6 In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max , and C min increased by about 35% in the presence of venlafaxine.

The

2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving venlafaxine hydrochloride have regular monitoring of blood pressure (see WARNINGS ). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine co-administration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4 Venlafaxine did not inhibit CYP3A4 in vitro . This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2 Venlafaxine did not inhibit CYP1A2 in vitro . This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9 Venlafaxine did not inhibit CYP2C9 in vitro . In vivo , venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19 Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS . CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required (see CONTRAINDICATIONS and WARNINGS ).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including venlafaxine hydrochloride, and the potential for serotonin syndrome, caution is advised when venlafaxine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort (see WARNINGS : Serotonin Syndrome ). If concomitant treatment of venlafaxine hydrochloride with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome ). The concomitant use of venlafaxine hydrochloride with tryptophan supplements is not recommended (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome ).

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of venlafaxine hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome ). Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/ mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine hydrochloride treatment.

Postmarketing Spontaneous Drug Interaction Reports

See ADVERSE REACTIONS, Postmarketing Reports .