Venlafaxine Tablets, USP, Rx only

/Venlafaxine Tablets, USP, Rx only
Venlafaxine Tablets, USP, Rx only2018-09-06T09:12:40+00:00

Prescription Drug Name:

Venlafaxine Tablets, USP, Rx only

ID:

6e2ca57c-94b2-75db-e053-2a91aa0a6586

Code:

34391-3

Suicidality and Antidepressant Drugs


id: 6e2ca57c-94b3-75db-e053-2a91aa0a6586
displayName: BOXED WARNING SECTION
FDA Article Code: 34066-1

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of venlafaxine  tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Venlafaxine tablets are not approved for use in pediatric patients.
(See
WARNINGS
: Clinical Worsening and Suicide Risk,
PRECAUTIONS: Information for Patients
, and
PRECAUTIONS: Pediatric Use
)

DESCRIPTION


id: 6e2ca57c-94b4-75db-e053-2a91aa0a6586
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Venlafaxine hydrochloride USP is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C
17H
27NO
2HCl. Its molecular weight is 313.87.
The structural formula is shown below.

 

 

Venlafaxine hydrochloride USP 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.

Compressed tablets contain venlafaxine hydrochloride USP equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxide red, iron oxide yellow,lactose monohydrate, magnesium stearate and crospovidone.

CLINICAL PHARMACOLOGY*


id: 6e2ca57c-94b5-75db-e053-2a91aa0a6586
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Pharmacodynamics

The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or ⛙-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.

 

Pharmacokinetics

Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethyl venlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV.

 

The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. 

 

Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. 

 

Age and Gender

A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see
DOSAGE AND ADMINISTRATION).

 

Liver Disease

In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. 

 

In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. 

Dosage adjustment is necessary in these hepatically impaired patients (see
DOSAGE AND ADMINISTRATION).

 

Renal Disease

In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. 

Dosage adjustment is necessary in these patients (see
DOSAGE AND ADMINISTRATION).

CLINICAL TRIALS


id: 6e2ca57c-94b6-75db-e053-2a91aa0a6586
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5

The efficacy of venlafaxine  tablets as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with venlafaxine tablets in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed venlafaxine tablets doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose venlafaxine tablets doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, venlafaxine tablets were shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. 

 

While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

 

In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on venlafaxine hydrochloride extended release capsules (75, 150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine hydrochloride extended release capsules dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued venlafaxine hydrochloride extended release capsules treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. 

 In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on venlafaxine tablets (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same venlafaxine tablet dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued venlafaxine tablet treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

INDICATIONS AND USAGE


id: 6e2ca57c-94b7-75db-e053-2a91aa0a6586
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Venlafaxine tablets are indicated for the treatment of major depressive disorder. 

 

The efficacy of venlafaxine tablets in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see

CLINICAL TRIALS
).

 

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The efficacy of venlafaxine hydrochloride extended release capsules in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of venlafaxine tablets in maintaining an antidepressant response in patients with recurrent depression 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 tablets/ venlafaxine hydrochloride extended release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS


id: 6e2ca57c-94b8-75db-e053-2a91aa0a6586
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

The use of MAOIs intended to treat psychiatric disorders with venlafaxine tablets or within 7 days of stopping treatment with venlafaxine tablets is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine tabletswithin 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see
WARNINGS and
DOSAGE AND ADMINISTRATION).

Starting venlafaxine tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see
WARNINGS and
DOSAGE AND ADMINISTRATION).

WARNINGS


id: 6e2ca57c-94b9-75db-e053-2a91aa0a6586
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

 

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided inTable 1.

 Table 1

Age

Range

Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
 Increases Compared to Placebo
<18 14 additional cases
18 to 24 5 additional cases
Decreases Compared to Placebo
25 to 64 1 fewer case
>65 6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. 

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

 

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a  course of drug therapy, or at times of dose changes, either increases or decreases. 

 

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and / or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. 

 

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. 

 

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see
PRECAUTIONS and
DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with
venlafaxine tablets, for a description of the risks of discontinuation of venlafaxine tablets). 

 

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.  Prescriptions for venlafaxine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 

 

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that venlafaxine tablets are not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including venlafaxine tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of venlafaxine tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Venlafaxine tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine tablets. Venlafaxine tablets should be discontinued before initiating treatment with the MAOI (see
CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

If concomitant use of venlafaxine tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with venlafaxine tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Sustained Hypertension

Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥90 mm Hg
and ≥10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine:

Probability of Sustained Elevation in SDBP

(Pool of Premarketing Venlafaxine Studies)

Treatment Group Incidence of Sustained Elevation in SDBP
Venlafaxine
< 100 mg/day 3%
101 to 200 mg/day 5%
201 to 300 mg/day 7%
> 300 mg/day 13%
Placebo 2%
An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. 

ADVERSE REACTIONS


id: 6e2ca57c-94c7-75db-e053-2a91aa0a6586
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Associated with Discontinuation of Treatment

Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included:

CNS Venlafaxine Placebo
Somnolence 3% 1%
Insomnia 3% 1%
Dizziness 3%
Nervousness 2%
Dry mouth 2%
Anxiety 2% 1%
Gastrointestinal
Nausea 6% 1%
Urogenital
Abnormal ejaculation* 3%
Other
Headache 3% 1%
Asthenia 2%
Sweating 2%
* Percantage based on the number of males

— Less than 1%

Incidence in Controlled Trials

Commonly Observed Adverse Events in Controlled Clinical Trials

The most commonly observed adverse events associated with the use of venlafaxine tablets (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for venlafaxine tablets at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men.

 

Adverse Events Occurring at an Incidence of 1% or More Among venlafaxine tablets-Treated Patients

The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among venlafaxine tablets-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

 

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

 

TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials
1

Body System Preferred Term Venlafaxine tablets

(n = 1033)

Placebo

(n = 609)

 Body as a Whole Headache 25% 24%
Asthenia 12% 6%
Infection 6% 5%
Chills 3%
Chest pain 2% 1%
Trauma 2% 1%
Cardiovascular Vasodilatation 4% 3%
Increased blood pressure / hypertension 2%
Tachycardia 2%
Postural hypotension 1%
Dermatological Sweating 12% 3%
Rash 3% 2%
Pruritus 1%
Gastrointestinal Nausea 37% 11%
Constipation 15% 7%
Anorexia 11% 2%
Diarrhea 8% 7%
Vomiting 6% 2%
Dyspepsia 5% 4%
Flatulence 3% 2%
Metabolic Weight loss 1%
Nervous System Somnolence 23% 9%
Dry mouth 22% 11%
Dizziness 19% 7%
Insomnia 18% 10%
Nervousness 13% 6%
Anxiety 6% 3%
Tremor 5% 1%
Abnormal dreams 4% 3%
Hypertonia 3% 2%
Paresthesia 3% 2%
Libido decreased 2%
Agitation 2%
Confusion 2% 1%
Thinking abnormal 2% 1%
Depersonalization 1%
Depression 1%
Urinary retention 1%
Twitching 1%
Respiration Yawn 3%
Special Senses Blurred vision 6% 2%
Taste perversion 2%
Tinnitus 2%
Mydriasis 2%
Urogenital System Abnormal ejaculation / orgasm 12%
2

2
Impotence 6%
2

2
Urinary frequency 3% 2%
Urination impaired 2%
Orgasm disturbance 2%
3

3
1 Events reported by at least 1% of patients treated with venlafaxine tablets are included, and are rounded to the nearest %. Events for which the venlafaxine tablets incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea
3.

Incidence less than 1%.

2 Incidence based on number of male patients.

3 Incidence based on number of female patients.

Dose Dependency of Adverse Events

A comparison of adverse event rates in a fixed-dose study comparing venlafaxine tablets75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine tablets use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine tablet group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. 

TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial

 Venlafaxine tablets (mg/day)
Body System/Preferred Term Placebo (n = 92) 75 (n = 89) 225 (n=89) 375 (n=88)
Body as a Whole
Abdominal pain 3.3% 3.4% 2.2% 8.0%
Asthenia 3.3% 16.9% 14.6% 14.8%
Chills 1.1% 2.2% 5.6% 6.8%
Infection 2.2% 2.2% 5.6% 2.3%
Cardiovascular System
Hypertension 1.1% 1.1% 2.2% 4.5%
Vasodilation 0.0% 4.5% 5.6% 2.3%
Digestive System
Anorexia 2.2% 14.6% 13.5% 17.0%
Dyspepsia 2.2% 6.7% 6.7% 4.5%
Nausea 14.1% 32.6% 38.2% 58.0%
Vomiting 1.1% 7.9% 3.4% 6.8%
Nervous System
Agitation 0.0% 1.1% 2.2% 4.5%
Anxiety 4.3% 11.2% 4.5% 2.3%
Dizziness 4.3% 19.1% 22.5% 23.9%
Insomnia 9.8% 22.5% 20.2% 13.6%
Libido decreased 1.1% 2.2% 1.1% 5.7%
Nervousness 4.3% 21.3% 13.5% 12.5%
Somnolence 4.3% 16.9% 18.0% 26.1%
Tremor 0.0% 1.1% 2.2% 10.2%
Respiratory System
Yawn 0.0% 4.5% 5.6% 8.0%
Skin and Appendages
Sweating 5.4% 6.7% 12.4% 19.3%
Special Senses
Abnormality of accommodation 0.0% 9.1% 7.9% 5.6%
Urogenital System
Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5%
Impotence 0.0% 5.8% 2.1% 3.6%
(Number of men) (n = 63) (n = 52) (n = 48) (n = 56)

Adaptation to Certain Adverse Events

Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth).

 

Vital Sign Changes

Venlafaxine tablet treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. 

 

In controlled clinical trials, venlafaxine tablets were associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see
WARNINGS).

 

Laboratory Changes

Of the serum chemistry and hematology parameters monitored during clinical trials with venlafaxine tablets, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with venlafaxine tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL.

 

Patients treated with venlafaxine tablets 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 (see 
PRECAUTIONS General
– Serum Cholesterol Elevation).

 

ECG Changes

In an analysis of ECGs obtained in 769 patients treated with venlafaxine tablets and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for venlafaxine  tablets. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see
PRECAUTIONS, General,
Use in Patients with Concomitant Illness).

 

Other Events Observed During the Premarketing Evaluation of Venlafaxine

During its premarketing assessment, multiple doses of venlafaxine tablets were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of venlafaxine hydrochloride extended release capsules, multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and venlafaxine  tablets wereadministered to 96 patients. During its premarketing assessment, multiple doses of venlafaxine hydrochloride extended release capsuleswere also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine tablets only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. 

 

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it.

 

Events are further categorized by body system and listed in order of decreasing frequency using the following definitions:
frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients;
infrequent adverse events are those occurring in 1/100 to 1/1000 patients;
rare events are those occurring in fewer than 1/1000 patients.

 

Body as a whole –
Frequent: accidental injury, chest pain substernal, neck pain;
Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome;
Rare: appendicitis, bacteremia, carcinoma, cellulitis.

 

Cardiovascular system –
Frequent: migraine;
Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis;
Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor.

 

Digestive system –
Frequent: eructation;
Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration;
Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration.

 

Endocrine system –
Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.

 

Hemic and lymphatic system –
Frequent: ecchymosis;
Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia;
Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura.

 

Metabolic and nutritional –
Frequent: edema, weight gain;
Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst;
Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.

 

Musculoskeletal system –
Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis;
Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.

 

Nervous system –
Frequent: trismus, vertigo;
Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor;
Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis.

 

Respiratory system –
Frequent: bronchitis, dyspnea;
Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration;
Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.

 

Skin and appendages –
Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria;
Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae.

 

Special senses –
Frequent: abnormality of accommodation, abnormal vision;
Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect;
Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis.

 

Urogenital system –
Frequent: metrorrhagia*, prostatic disorder (prostatitis and enlarged prostate)*, vaginitis*;
Infrequent: albuminuria, amenorrhea*, cystitis, dysuria, hematuria, leukorrhea*, menorrhagia*, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage*;
Rare: abortion*, anuria, balanitis*, breast discharge, breast engorgement, breast enlargement, endometriosis*, fibrocystic breast, calcium crystalluria, cervicitis*, ovarian cyst*, prolonged erection*, gynecomastia (male)*, hypomenorrhea*, kidney calculus, kidney pain, kidney function abnormal, female lactation*, mastitis, menopause*, oliguria, orchitis*, pyelonephritis, salpingitis*, urolithiasis, uterine hemorrhage*, uterine spasm*, vaginal dryness*. 

 

* Based on the number of men and women as appropriate.

Postmarketing Reports

Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). 

 There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

DRUG ABUSE AND DEPENDENCE


id: 6e2ca57c-94c8-75db-e053-2a91aa0a6586
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9

Controlled Substance Class

Venlafaxine hydrochloride is not a controlled substance.

 

Physical and Psychological Depedence

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. 

 

Discontinuation effects have been reported in patients receiving venlafaxine (see
DOSAGE AND ADMINISTRATION).

While venlafaxine  tablets have not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine tablets (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

OVERDOSAGE


id: 6e2ca57c-94c9-75db-e053-2a91aa0a6586
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Human Experience

There were 14 reports of acute overdose with venlafaxine tablets, either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of venlafaxine tablets 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 ⛤g/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 ⛤g/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.

In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in over dosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. 

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in over dosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine tablets should be written for the smallest quantity of tablets 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 over dosage with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).

DOSAGE AND ADMINISTRATION*


id: 6e2ca57c-94ca-75db-e053-2a91aa0a6586
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Initial Treatment

The recommended starting dose for venlafaxine tablet is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see
PRECAUTIONS, General, Use in Patients with Concomitant Illness).

 

Special Populations

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to venlafaxine tablets, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see
PRECAUTIONS). When treating pregnant women with venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. 

 

Dosage for Patients with Hepatic Impairment

Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see

CLINICAL PHARMACOLOGY
), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.

 

Dosage for Patients with Renal Impairment

Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see

CLINICAL PHARMACOLOGY
), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients.

 

Dosage for Elderly Patients

No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

 

Maintenance Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride extended release capsules (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of venlafaxine tablets in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see 



CLINICAL TRIALS


). Based on these limited data, it is not known whether or not the dose of venlafaxine tablets / 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.

Discontinuing venlafaxine tablets

Symptoms associated with discontinuation of venlafaxine tablets, other SNRIs, and SSRIs, have been reported (see
PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. 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.

SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR


id: 6e2ca57c-94cb-75db-e053-2a91aa0a6586
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5

Switching a Patient 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 tablets. Conversely, at least 7 days should be allowed after stopping venlafaxine tablets before starting an MAOI intended to treat psychiatric disorders (see
CONTRAINDICATIONS).


Use of Venlafaxine tablets With Other MAOls, Such as Linezolid or Methylene Blue:Do not start venlafaxine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see
CONTRAINDICATIONS).

In some cases, a patient already receiving therapy with venlafaxine tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment 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 tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored 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 tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see
WARNINGS).

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 with venlafaxine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see
WARNINGS).

HOW SUPPLIED*


id: 6e2ca57c-94cc-75db-e053-2a91aa0a6586
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Venlafaxine Tablets, USP are available containing 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg of venlafaxine.

25 mg, peach colored, round shape, flat, beveled edge, uncoated tablets debossed with ‘175’ on one side and breakline on other side.

NDC 62332-008-30 bottle of 30 tablets.

NDC 62332-008-31 bottle of 100 tablets.

NDC 62332-008-91 bottle of 1000 tablets.

37.5 mg, peach colored, round shape, flat, beveled edge, uncoated tablets debossed with ‘176’ on one side and breakline on other side.

NDC 62332-009-30 bottle of 30 tablets.

NDC 62332-009-31 bottle of 100 tablets.

NDC 62332-009-91 bottle of 1000 tablets.

50 mg, peach colored, round shape, flat, beveled edge, uncoated tablets debossed with ‘L177’ on one side and breakline on other side.

NDC 62332-010-30 bottle of 30 tablets.

NDC 62332-010-31 bottle of 100 tablets.

NDC 62332-010-91 bottle of 1000 tablets.

75 mg, peach colored, round shape, flat, beveled edge, uncoated tablets debossed with ‘L178’ on one side and breakline on other side.

NDC 62332-011-30 bottle of 30 tablets.

NDC 62332-011-31 bottle of 100 tablets.

NDC 62332-011-91 bottle of 1000 tablets.

100 mg, peach colored, round shape, flat, beveled edge, uncoated tablets debossed with ‘L179’ on one side and breakline on other side.

NDC 62332-012-30 bottle of 30 tablets.

NDC 62332-012-31 bottle of 100 tablets.

NDC 62332-012-91 bottle of 1000 tablets.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] in a dry place.


Dispense in a well-closed container as defined in the USP.

* Different strengths of the drug product mentioned in the package insert are based on Venlafaxine base.

Medication Guide available at
http://www.alembicusa.com/medicationguide.aspx or call 1-866 210 9797. 

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India

Manufactured for:

Alembic Pharmaceuticals, Inc.

750 Route 202, Bridgewater, NJ 08807

USA

Revised: 03/2017

Medication Guide


id: 6e2ca57c-94cd-75db-e053-2a91aa0a6586
displayName: SPL MEDGUIDE SECTION
FDA Article Code: 42231-1

Venlafaxine

(ven-la-fax-een) Tablets, USP
Read the Medication Guide that comes with venlafaxine tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about venlafaxine tablets?

Venlafaxine tablets
and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

• Venlafaxine tablets and other  antidepressant medicines may  increase suicidal  thoughts or  actions
in some children, teenagers,  or young adults
within the first few  months of treatment or when the  dose is changed.

• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.

• Watch for these changes and call your healthcare provider right away if you notice:

• New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.

• Pay particular attention to such changes when venlafaxine tablets is started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

• attempts to commit suicide

• acting on dangerous impulses

• acting aggressive or violent

• thoughts about suicide or dying

• new or worse depression

• new or worse anxiety or panic attacks

• feeling agitated, restless, angry or irritable

• trouble sleeping

• an increase in activity or talking more than what is normal for you

• other unusual changes in behavior or mood

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Venlafaxine tablets may be associated with these serious side effects: 2. Serotonin Syndrome

This condition can be life-threatening and may include:

• agitation, hallucinations, coma or other changes in mental status

• coordination problems or muscle twitching (overactive reflexes)

• racing heartbeat, high or low blood pressure

• sweating or fever

• nausea, vomiting, or diarrhea

• muscle rigidity

3. Changes in blood pressure.

 Venlafaxine tablets may:

• increase your blood pressure. Control high blood pressure before starting treatment and monitor blood pressure regularly

4. Enlarged pupils (mydriasis).

5. Anxiety and insomnia.

6. Changes in appetite or weight.

• children and adolescents should have height and weight monitored during treatment

7. Manic/hypomanic episodes:

• greatly increased energy

• severe trouble sleeping

• racing thoughts

• reckless behavior

• unusually grand ideas

• excessive happiness or irritability

• talking more or faster than usual

8. Low salt (sodium) levels in the blood.

 Elderly people may be at greater risk  for this. Symptoms may include:

• Headache

• weakness or feeling unsteady

• confusion, problems concentrating or thinking or memory problems

9. Seizures or convulsions.

10. Abnormal bleeding: venlafaxine tablets
and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a nonsteroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

11. Elevated cholesterol.

12. Lung disease and pneumonia: Venlafaxine tablets may cause rare lung problems. Symptoms include:

• worsening shortness of breath

• cough

• chest discomfort

13. Severe allergic reactions:

• trouble breathing

• swelling of the face, tongue, eyes or mouth

• rash, itchy welts (hives) or blisters, alone or with fever or joint pain 14. Visual Problems

• eye pain

• changes in vision

• swelling or redness in or around the eye.

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Do not stop venlafaxine tablets without first talking to your healthcare provider. Stopping venlafaxine tablets too quickly or changing from another antidepressant too quickly may cause serious symptoms including:

• anxiety, irritability

• feeling tired, restless or problems sleeping

• headache, sweating, dizziness

• electric shock-like sensations, shaking, confusion, nightmares

• vomiting, nausea, diarrhea What is venlafaxine tablet?

Venlafaxine tablet
is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.

Talk to your healthcare provider if you do not think that your condition is getting better with venlafaxine tablets treatment.

Who should not take venlafaxine tablets?

Do not take
venlafaxine tablets if you:

• are allergic to
venlafaxine tablets or any of the ingredients in
venlafaxine tablets.

See the end of this Medication Guide for a complete list of ingredients in
venlafaxine tablets.

• have uncontrolled narrow-angle glaucoma

• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.

• Do not take an MAOI within 7 days of stopping
venlafaxine tablets unless directed to do so by your physician.

• Do not start
venlafaxine tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take venlafaxine tablets close in time to an MAOI may have serious or even life threatening side effects. Get medical help right away if you have any of these symptoms:

• high fever

• uncontrolled muscle spasms

• stiff muscles

• rapid changes in heart rate or blood pressure

• confusion

• loss of consciousness (pass out) What should I tell my healthcare provider before taking venlafaxine tablets? Ask if you are not sure.

Before starting
venlafaxine tablets, tell your healthcare provider if you:

• Are taking certain drugs such as:

• Medicines used to treat migraine headaches such as:

o Triptans

• Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:

o tricyclic antidepressants

o lithium

o SSRIs

o SNRIs

o antipsychotic drugs

• Medicines used to treat pain such as:

o Tramadol

• Medicines used to thin your blood such as:

o Warfarin

• Medicines used to treat heartburn such as:

o Cimetidine

• Over-the-counter medicines or supplements such as:

o Aspirin or other NSAIDs

o Tryptophan

o St. John’s Wort

• have heart problems

• have diabetes

• have liver problems

• have kidney problems

• have thyroid problems

• have glaucoma

• have or had seizures or convulsions

• have bipolar disorder or mania

• have low sodium levels in your blood

• have high blood pressure

• have high cholesterol

• have or had bleeding problems

• are pregnant or plan to become pregnant. It is not known if
venlafaxine tablets will harm your unborn

• baby

• Talk to your healthcare provider about the benefits and risks of treating depression during

• pregnancy.

• are breast-feeding or plan to breast-feed. Some venlafaxine hydrochloride may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking
venlafaxine tablets.

Tell your healthcare provider about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Venlafaxine tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take
venlafaxine tablets with your other medicines. Do not start or stop any medicine while taking venlafaxine tablets without talking to your healthcare provider first.

 If you take venlafaxine tablets, you should not take any other medicines that contain (venlafaxine) including: venlafaxine HCl.

How should I take venlafaxine tablets?

• Take venlafaxine tablets exactly as prescribed. Your healthcare provider may need to change the dose of
venlafaxine tablets until it is the right dose for you.

• 
Venlafaxine tablet is to be taken with food.

• If you miss a dose of venlafaxine tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of
venlafaxine tablets at the same time.

• If you take too much
venlafaxine tablets, call your healthcare provider or poison control center right away, or get emergency treatment.

• When switching from another antidepressant to
venlafaxine tablets your doctor may want to lower the dose of the initial antidepressant first to avoid side effects.

What should I avoid while taking venlafaxine tablets?

Venlafaxine tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how
venlafaxine tablets affects you. Do not drink alcohol while using venlafaxine tablets.

What are the possible side effects of venlafaxine tablets?

Venlafaxine tablets
may cause serious side effects, including:

• See “What is the most important information I should know about
venlafaxine tablets?”

• Increased cholesterol- have your cholesterol checked regularly

• Newborns whose mothers take
venlafaxine tablets in the third trimester may have problems right after birth including:

• problems feeding and breathing

• seizures

• shaking, jitteriness or constant crying

• Narrow-angle glaucoma/enlarged pupils. Check eye pressure regularly if you:

• have a history of increased eye pressure

• are at risk for certain types of glaucoma

Common possible side effects in people who take venlafaxine tablets include:

• unusual dreams

• sexual problems

• loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth

• feeling tired, fatigued or overly sleepy

• change in sleep habits, problems sleeping

• yawning

• tremor or shaking

• dizziness, blurred vision

• sweating

• feeling anxious, nervous or jittery

• headache

• increase in heart rate

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of venlafaxine tablets. For more information, ask your healthcare provider orpharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO FDA AT 1-800-FDA-1088.

How should I store venlafaxine tablets?

• Store
venlafaxine tablets at room temperature between 68°F and 77°F (20°C to 25°C).

• Keep venlafaxine tablets in a dry place.

Keep venlafaxine tablets and all medicines out of the reach of children.

General information about venlafaxine tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use venlafaxine tablets for a condition for which it was not prescribed. Do not give
venlafaxine tablets to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about
venlafaxine tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about
venlafaxine tablets that is written for healthcare professionals.

For more information about venlafaxine tablets call  Alembic Pharmaceuticals Limited 1-866 210 9797.

What are the ingredients in venlafaxine tablets?

Active ingredient: (venlafaxine)

Inactive ingredients:

• 
Tablets: cellulose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate and crospovidone. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. The brands listed are the registered trademarks of their respective owners.

Medication Guide available at
http://www.alembicusa.com/medicationguide.aspx or call 1-866 210 9797.

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India Manufactured for:

Alembic Pharmaceuticals, Inc.

750 Route 202, Bridgewater, NJ 08807

USA

Revision Date: 03/2017

PRINCIPAL DISPLAY PANEL


id: 6e2ca57c-94ce-75db-e053-2a91aa0a6586
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

DRUG: venlafaxine GENERIC: venlafaxine DOSAGE: TABLET ADMINSTRATION: ORAL NDC: 70518-1245-0 COLOR: orange SHAPE: ROUND SCORE: Two even pieces SIZE: 10 mm IMPRINT: L179 PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): VENLAFAXINE HYDROCHLORIDE 100mg in 1 INACTIVE INGREDIENT(S): CELLULOSE, MICROCRYSTALLINE
CROSPOVIDONE
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE