Effexor Xr (Venlafaxine Hydrochloride)

Check Drug InteractionsCheck known drug interactions.

Dosage & 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 General Administration Information

Administer Effexor XR 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).

).
* •When discontinuing treatment, reduce the dose gradually (

2.10 Discontinuing Treatment with Effexor XR

A gradual reduction in the dose, rather than abrupt cessation, is recommended when discontinuing therapy with Effexor XR. In clinical studies with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary. In some patients, discontinuation may need to occur over a period of several months

[see

Warnings and Precautions (5.7)

]

5.7 Discontinuation Syndrome

Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock‑like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.

There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in Effexor XR dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of Effexor XR.

During marketing of Effexor XR, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures.

Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months

[see Dosage and Administration (2.10)]

).
* •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 Dosage Recommendations for Patients with Renal Impairment

Reduce the Effexor XR total daily dose by 25% to 50% in patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Reduce the total daily dose by 50% or more in patients undergoing hemodialysis or with severe renal impairment (CLcr <30 mL/min). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage is recommended in some patients

[see Use in Specific Populations (8.7)]

).
* •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 Dosage Recommendations for Patients with Hepatic Impairment

Reduce the Effexor XR total daily dose by 50% in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Reduce the total daily dose by 50% or more in patients with severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis

[see Use in Specific Populations (8.6)]

Effexor XR prescribing information

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors

[see

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in PediatricEffexor XR is not approved in pediatric patients.and Adult Patients
Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated
	Increases Compared to Placebo
<18 years old	14 additional patients
18-24 years old	5 additional patients
	Decreases Compared to Placebo
25-64 years old	1 fewer patient
≥65 years old	6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Effexor XR, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

]

. Effexor XR is not approved for use in pediatric patients

[see

8.4 Pediatric Use

Safety and effectiveness of Effexor XR in pediatric patients have not been established.

Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support use in pediatric patients.

In the studies conducted in pediatric patients ages 6 to 17 years, the occurrence of blood pressure and cholesterol increases was considered to be clinically relevant in pediatric patients and was similar to that observed in adult patients

[see

Warnings and Precautions (5.3)

, Adverse Reactions (6.1)]

. The following adverse reactions were also observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height

[see

Warnings and Precautions (5.10

5.11)

Decreased appetite and weight loss were observed in placebo-controlled studies of pediatric patients 6 to 17 years.

In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients

[see Boxed Warning,

Warnings and Precautions (5.1)

]

Warnings and Precautions (

5.2 Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Effexor XR, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs

[see Contraindications (4), Drug Interactions (7.1)]

. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Effexor XR with MAOIs is contraindicated. In addition, do not initiate Effexor XR in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR, discontinue Effexor XR before initiating treatment with the MAOI

[see Contraindications (4), Drug Interactions (7.1)]

Monitor all patients taking Effexor XR for the emergence of serotonin syndrome. Discontinue treatment with Effexor XR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Effexor XR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti‑coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case‑control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage

[see Use in Specific Populations (8.1)]

Inform patients about the increased risk of bleeding associated with the concomitant use of Effexor XR and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Effexor XR

) 8/2023

Effexor XR is indicated in adults for the treatment of:

•Major Depressive Disorder (MDD)

[see

14.1 Major Depressive Disorder

The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, Effexor XR demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, Effexor XR also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing Effexor in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of Effexor over placebo based on the HAM-D-21 total score. The mean dose in completers was 350 mg per day (study 3).

In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on Effexor XR (75, 150, or 225 mg, once daily every morning) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open-label 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 Effexor XR treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4).

In a second longer term trial, adult outpatients with MDD, 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 Effexor [100 to 200 mg per day, on a twice daily schedule] were randomized to continuation of their same Effexor 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 Effexor treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5).

Table 18: Primary Efficacy Results for Studies in Major Depressive Disorder in Adults (Studies 1, 2, 3)
Study Number	Treatment Group		Primary Efficacy Measure: HAM-D Score
		Mean Baseline Score (SD)	LS Mean Change from Baseline	Placebo Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95%CI)
SD=standard deviation; LS Mean=least-squares mean; CI=confidence interval.
Study 1	Effexor (XR 75-225 mg/day)Doses statistically significantly superior to placebo.	24.5	-11.7	-4.45 (-6.66, -2.25)
Study 1	Placebo	23.6	-7.24	-
Study 2	Effexor (XR 75-225 mg/day)	24.5	-15.11	-6.40 (-8.45, -4.34)
Study 2	Placebo	24.9	-8.71
Study 3	Effexor (IR 150-375 mg/day)	28.2 (0.5)	-14.9	-10.2 (-14.4, -6.0)
Study 3	Placebo	28.6 (0.6)	-4.7	-

]

•Generalized Anxiety Disorder (GAD)

[see

14.2 Generalized Anxiety Disorder

The efficacy of Effexor XR as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD.

In one 8-week study, Effexor XR demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied.

Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating Effexor XR doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses.

Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

Table 19: Primary Efficacy Results for Studies in Generalized Anxiety Disorder in Adults (Studies 1, 2, 3, 4)
Study Number	Treatment Group	Primary Efficacy Measure: HAM-A Score
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE) Doses statistically significantly superior to placebo.	Placebo Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI)
SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval.
Study 1	Ven XR 75 mg	24.7	-11.1 (0.95)	-1.5 (-3.8, 0.8)
	Ven XR 150 mg	24.5	-11.7 (0.87)	-2.2 (-4.5, 0.1)
	Ven XR 225 mg	23.6	-12.1 (0.81)	-2.6 (-4.9, -0.3)
	Placebo	24.1	-9.5 (0.85)
Study 2	Ven XR 75 mg	23.7	-10.6 (0.82)	-2.6 (-4.6, -0.5)
	Ven XR 150 mg	23.0	-9.8 (0.86)	-1.7 (-3.8, 0.3)
	Placebo	23.7	-8.0 (0.73)
Study 3	Ven XR 37.5 mg	26.6 (0.4)	-13.8	-2.8 (-5.1, -0.6)
	Ven XR 75 mg	26.3 (0.4)	-15.5	-4.6 (-6.9, -2.3)
	Ven XR150 mg	26.3 (0.4)	-16.4	-5.5 (-7.8, -3.1)
	Placebo	26.7 (0.5)	-11.0
Study 4	Ven XR 75-225 mg	25.0	-13.4 (0.79)	-4.7 (-6.6, -2.9)
Study 4	Placebo	24.9	-8.7 (0.70)

]

•Social Anxiety Disorder (SAD)

[see

14.3 Social Anxiety Disorder (Also Known as Social Phobia)

The efficacy of Effexor XR as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1-4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5).

In these five studies, Effexor XR was statistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to the 75 mg per day group in the 6-month study.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

Table 20: Primary Efficacy Results for Studies in Social Anxiety Disorder in Adults (Studies 1, 2, 3, 4, 5)
Study Number	Treatment Group	Primary Efficacy Measure: LSAS Score
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI)
SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval.
Study 1	Ven XR (75-225 mg)Doses statistically significantly superior to placebo.	91.1	-31.0 (2.22)	11.2 (-5.3, -17.1)
Study 1	Placebo	86.7	-19.9 (2.22)	-
Study 2	Ven XR (75-225 mg)	90.8	-32.8 (2.69)	-10.7 (-3.7, -17.6)
Study 2	Placebo	87.4	-22.1 (2.66)	-
Study 3	Ven XR (75-225 mg)	83.2	-36.0 (2.35)	-16.9 (-22.6, -11.2)
Study 3	Placebo	83.6	-19.1 (2.40)	-12.7 (-6.5, -19.0)
Study 4	Ven XR (75-225 mg)	86.2	-35.0 (2.64)	-14.6 (-21.8, -7.4)
Study 4	Placebo	86.1	-22.2 (2.47)
Study 5	Ven XR 75 mg	91.8	-38.1 (3.16)	-14.6 (-21.8, -7.4)
	Ven XR (150-225 mg)	86.2	-37.6 (3.05)	-14.1 (-21.3, -6.9)
	Placebo	89.3	-23.5 (3.08)

]

•Panic Disorder (PD)

[see

14.4 Panic Disorder

The efficacy of Effexor XR as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2).

Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, Effexor XR was statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established.

In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with Effexor XR (75 to 225 mg per day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a statistically significantly longer time to relapse.

Table 21: Primary Efficacy Results for Studies in Panic Disorder in Adults (Studies 1 and 2)
Study Treatment Group Number		Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks
		Percent of Patients Free of Full Symptom Panic Attack	Adjusted Odds Ratio Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model. 95% CI: 95% confidence interval without adjusting for multiple dose arms. to Placebo	Adjusted Odds Ratio 95% Confidence Interval
Study 1	Ven XR 75 mgDoses statistically significantly superior to placebo. Ven XR 150 mg Placebo	54.1% (85/157) 61.4% (97/158) 34.4% (53/154)	2.268 3.035 --	(1.43, 3.59) (1.91, 4.82) --
Study 2	Ven XR 75 mg Ven XR 225 mg Placebo	64.1% (100/156) 70.0% (112/160) 46.5% (73/157)	2.350 2.890 --	(1.46, 3.78) (1.80, 4.64) --

]

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 General Administration Information
Administer Effexor XR 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).
).
•When discontinuing treatment, reduce the dose gradually (
2.10 Discontinuing Treatment with Effexor XR
A gradual reduction in the dose, rather than abrupt cessation, is recommended when discontinuing therapy with Effexor XR. In clinical studies with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary. In some patients, discontinuation may need to occur over a period of several months
[see
Warnings and Precautions (5.7)
]
.
,
5.7 Discontinuation Syndrome
Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock‑like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.
There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in Effexor XR dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of Effexor XR.
During marketing of Effexor XR, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures.
Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months
[see Dosage and Administration (2.10)]
.
).
•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 Dosage Recommendations for Patients with Renal Impairment
Reduce the Effexor XR total daily dose by 25% to 50% in patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Reduce the total daily dose by 50% or more in patients undergoing hemodialysis or with severe renal impairment (CLcr <30 mL/min). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage is recommended in some patients
[see Use in Specific Populations (8.7)]
.
).
•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 Dosage Recommendations for Patients with Hepatic Impairment
Reduce the Effexor XR total daily dose by 50% in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Reduce the total daily dose by 50% or more in patients with severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis
[see Use in Specific Populations (8.6)]
.
).

Effexor XR^® is available in the following strengths:

•37.5 mg extended-release capsule: grey cap and peach body with “W” and “Effexor XR” on the cap and “37.5” on the body
•75 mg extended-release capsule: peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body
•150 mg extended-release capsule: dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body

Pregnancy:

Third trimester use may increase risk for symptoms of poor neonatal adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate (

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including Effexor XR, 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-research-programs/pregnancyregistry/antidepressants/

Risk Summary

Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage

[see Warnings and Precautions (5.4)and Clinical Considerations]

Available data from published epidemiologic studies on venlafaxine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes

(see Data)

. Available data from observational studies with venlafaxine have identified a potential increased risk for preeclampsia when used during mid to late pregnancy; exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage

(see Clinical Considerations)

. There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including Effexor XR, during pregnancy

(see Clinical Considerations)

In animal studies, there was no evidence of malformations or fetotoxicity following administration of venlafaxine during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m²basis. Postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m²) the maximum human daily dose.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical 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 Effexor XR in mid to late pregnancy may increase the risk for preeclampsia, and exposure to Effexor XR in the month before delivery may be associated with an increased risk of postpartum hemorrhage

[see Warnings and Precautions (5.4)]

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 Effexor XR 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 limitations may both fail to identify true findings and also identify findings that are not true.

Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted [adj] RR 1.57, 95% confidence interval [CI] 1.29-1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg per day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10-20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg per day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders.

Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24 [95% CI 1.69-2.97]). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64-1.76). The results of this study may be confounded by the effects of depression.

Animal Data

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m²basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m²) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m²basis.

When desvenlafaxine succinate, the major metabolite of venlafaxine, was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no fetal malformations were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day.

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