Venlafaxine Hydrochloride

RECENT MAJOR CHANGES Boxed Warning 8/2022 Dosage and Administration ( 2.10 ) 11/2021 Dosage and Administration ( 2.2 , 2.3 , 2.6 , 2.8 , 2.9 , 2.11 ) 8/2022 Warnings and Precautions ( 5.13 ) 9/2021 Warnings and Precautions ( 5.7 ) 11/2021 Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.5 , 5.6 , 5.7 , 5.8 ) 8/2022

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 d …

2 DOSAGE AND ADMINISTRATION . Indication Starting Dose Target Dose Maximum Dose MDD (2.2) 37.5 -75 mg/day 75 mg/day 225 mg/day GAD (2.3) 37.5-75 mg/day 75 mg/day 225 mg/day SAD (2.4) 75 mg/day 75 mg/day 75 mg/day PD (2.5) 37.5 mg/day 75 mg/day 225 mg/day Take once daily with food. Capsules should be taken whole; do not divide, crush, chew, or dissolve ( 2.1 ). When discontinuing treatment, reduce the dose gradually ( 2.10 , 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 ( 2.9 ). 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% ( 2.8 ). 2.1 General Administration Information Administer Venlafaxine hydrochloride extended-release capsules as 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) ] . Swallow capsules whole with fluid. Do not divide, crush, chew, or place in water. The capsule may also 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). 2.2 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. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more. 2.3 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. 2.4 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. 2.5 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. 2.6 Screen for Bipolar Disorder Prior to Starting Venlafaxine hydrochloride extended-release capsules Prior to initiating treatment with Venlafaxine hydrochloride extended-release capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)]. 2.7 Switching Patients from Venlafaxine Hydrochloride Tablets Patients with depression who are currently being treated with venlafaxine hydrochloride Tablets may be switched to Venlafaxine hydrochloride extended-release capsules at the nearest equivalent dose (mg per day), e.g., …

3 DOSAGE FORMS AND STRENGTHS Venlafaxine hydrochloride extended-release capsules, USP is available in the following strengths: • 37.5 mg extended-release capsule: White to off white spherical to oval pellets filled in size ‘3’ hard gelatin capsules with “ ” imprinted in grey ink on white opaque cap and “016” imprinted in black ink on grey colored body. • 75 mg extended-release capsule: White to off white spherical to oval pellets filled in size ‘2’ hard gelatin capsules with “ ” imprinted in grey ink on white opaque cap and “017” imprinted in black ink on peach colored body. • 100 mg extended-release capsule: White to off white spherical to oval pellets in size ‘1’ hard gelatin capsules with “ ” imprinted in grey ink on white opaque cap and “186” imprinted in black ink on red colored body • 150 mg extended-release capsule: White to off white spherical to oval pellets filled in size ‘0’ hard gelatin capsules with “ ” imprinted in grey ink on white opaque cap and “018” imprinted in black ink on orange colored body. Extended-release capsules: 37.5 mg, 75 mg, 100 mg and 150 mg ( 3 ). Image Image Image Image

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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]. 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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]. • 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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]. 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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]. 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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hypersensitivity [see Contraindications ( 4.1 )] • Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [see Warnings and Precautions ( 5.1 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] • Elevations in Blood Pressure [see Warnings and Precautions ( 5.3 )] • Abnormal 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, erectile dysfunction, and libido decreased ( 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in 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%), 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 to 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 0.2 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 only) and outpatient studies, fixed-dose, and titration studies. Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-Release Capsules in Premarketing Clinical Studies Indication Venlafaxine Hydrochloride …

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 …

8. Use in Specific Populations 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including venlafaxine hydrochloride extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research­programs/pregnancyregistry/antidepressants/. Risk Summary Available data from published epidemiologic studies on venlafaxine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes (see Data). Available data from observational studies with venlafaxine have identified a potential increased risk for preeclampsia when used during mid to late pregnancy; exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage (see Clinical Considerations). There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including venlafaxine hydrochloride extended-release capsules, during pregnancy (see Clinical Considerations). In animal studies, there was no evidence of malformations or fetotoxicity following administration of venlafaxine during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. Postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m2) the maximum human daily dose. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depression who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Exposure to venlafaxine in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage. Fetal/Neonatal Adverse Reactions Neonates exposed to SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SNRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS (5.2)]. Monitor neonates who were exposed to venlafaxine hydrochloride extended-release capsules in the third trimester of pregnancy for drug discontinuation syndrome (see Data). Data Human Data Published epidemiological studies of pregnant women exposed to venlafaxine have not established an increased risk of major birth defects, miscarriage or other adverse developmental outcomes. Methodological …

12.1 Mechanism of Action The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

11 DESCRIPTION Venlafaxine hydrochloride extended-release capsules, USP is an extended-release capsule for once-a-day oral administration that contains venlafaxine hydrochloride, a serotonin and norepinephrine reuptake inhibitor (SNRI). Venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C 17 H 27 NO 2 HCl. Its molecular weight is 313.86. The structural formula is shown as follows: Venlafaxine hydrochloride is a white to off-white crystalline solid, with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, 100 mg or 150 mg venlafaxine. Inactive ingredients consist of ethylcellulose, hypromellose and sugar spheres. The empty hard gelatin capsule shells contain gelatin and titanium dioxide. The 37.5 mg capsules also contain iron oxide black. The 75 mg capsules also contain FD&C red no. 3 and FD&C yellow no. 6. The 100 mg capsules also contain iron oxide red. The 150 mg capsules also contain iron oxide red and iron oxide yellow. The 37.5 mg, 75 mg, 100 mg and 150 mg capsules are imprinted with black and grey ink which contains iron black oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution. Grey ink also contains titanium dioxide. Venlafaxine Hydrochloride Extended-release Capsules, USP meets USP Dissolution Test 11. Image

OVERDOSAGE Human Experience Among the patients included in the premarketing evaluation of venlafaxine hydrochloride extended-release capsules, there were 2 reports of acute overdosage with venlafaxine hydrochloride extended-release capsules in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of venlafaxine hydrochloride extended-release capsules and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of venlafaxine hydrochloride extended-release capsules. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with venlafaxine hydrochloride extended-release capsules in panic disorder trials. One patient took 0.675 g of venlafaxine hydrochloride extended-release capsules once, and the other patient took 0.45 g of venlafaxine hydrochloride extended-release capsules for 2 days. No signs or symptoms were associated with either overdose, and no actions were taken to treat them. Among the patients included in the premarketing evaluation with venlafaxine hydrochloride tablets (immediate release), there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 mcg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mcg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QT c to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher preexisting burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic meas …

16 HOW SUPPLIED/STORAGE AND HANDLING Venlafaxine Hydrochlorid e Extended-Release Capsules USP , 37.5 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘3’) of opaque grey color cap and opaque peach color body imprinted with “E” on cap and “73” on the body with edible black ink. Bottles of 15 NDC 76420-630-15 (relabeled from NDC 65862-527-47) Bottles of 30 NDC 76420-630-30 (repackaged/relabeled from NDC 65862-527-xx/65862-527-30) Bottles of 60 NDC 76420-630-60 (repackaged from NDC 65862-527-xx) Bottles of 90 NDC 76420-630-90 (repackaged from NDC 65862-527-xx) Bottles of 100 NDC 76420-630-01 (relabeled from NDC 65862-527-01) Venlafaxine Hydrochlorid e Extended-Release Capsules USP , 75 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘1’) of opaque peach color cap and opaque peach color body imprinted with “E” on cap and “74” on the body with edible black ink. Bottles of 15 NDC 76420-631-15 (relabeled from NDC 65862-528-47) Bottles of 30 NDC 76420-631-30 (repackaged from NDC 65862-528-xx) Bottles of 60 NDC 76420-631-60 (repackaged from NDC 65862-528-xx) Bottles of 90 NDC 76420-631-90 (repackaged from NDC 65862-528-xx) Bottles of 10 NDC 76420-631-01 (relabeled from NDC 65862-528-01) Venlafaxine Hydrochlorid e Extended-Release Capsules USP , 150 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘0’) of opaque dark orange color cap and opaque dark orange color body imprinted with “E” on cap and “89” on the body with edible black ink. Bottles of 15 NDC 76420-632-15 (relabeled from NDC 65862-697-47) Bottles of 30 NDC 76420-632-30 (relabeled/repackaged from NDC 65862-697-30/65862-697-xx) Bottles of 60 NDC 76420-632-60 (repackaged from NDC 65862-697-xx) Bottles of 90 NDC 76420-632-90 (repackaged from NDC 65862-697-xx) Bottles of 100 NDC 76420-632-01 (relabeled from NDC 65862-697-01) Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]