Effexor XR: Package Insert / Prescribing Info

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).

2.2 Major Depressive Disorder

For most patients, the recommended starting dose for Effexor XR is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 4 days. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more.

2.3 Generalized Anxiety Disorder

For most patients, the recommended starting dose for Effexor XR is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 4 days.

2.4 Social Anxiety Disorder (Social Phobia)

The recommended dose is 75 mg per day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.

2.5 Panic Disorder

The recommended starting dose is 37.5 mg per day of Effexor XR for 7 days. Patients not responding to 75 mg per day may benefit from dose increases to a maximum of approximately 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 7 days.

2.6 Screen for Bipolar Disorder Prior to Starting Effexor XR

Prior to initiating treatment with Effexor XR, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)].

2.7 Switching Patients from Effexor Tablets

Patients with depression who are currently being treated with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary.

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)].

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)].

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)].

2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of Effexor XR. In addition, at least 7 days must elapse after stopping Effexor XR before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2), and Drug Interactions (7.1)].

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.

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.

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, 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.

5.3 Elevated Blood Pressure

In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension [see Adverse Reactions (6.1)].

Monitor blood pressure before initiating treatment with Effexor XR and regularly during treatment. Control pre-existing hypertension before initiating treatment with Effexor XR. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with Effexor XR. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure.

Across all clinical studies with Effexor, 1.4% of patients in the Effexor XR treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups [see Adverse Reactions (6.1)]. Treatment with Effexor XR was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits [see Adverse Reactions (6.1)]. An insufficient number of patients received mean doses of Effexor XR over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including 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.

Inform patients about the 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.

5.5 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Effexor XR, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with Effexor XR or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in Effexor XR treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Effexor XR, screen for any personal or family history of bipolar disorder, mania, or hypomania.

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)].

5.8 Seizures

Cases of seizure have been reported with venlafaxine therapy. Effexor XR has not been systematically evaluated in patients with seizure disorder. Effexor XR should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia

Hyponatremia can occur as a result of treatment with SNRIs, including Effexor XR. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Consider discontinuation of Effexor XR in patients with symptomatic hyponatremia, and institute appropriate medical intervention.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.10 Weight and Height Changes in Pediatric Patients

5.11 Appetite Changes in Pediatric Patients

Decreased appetite (reported as anorexia) was more commonly observed in Effexor XR treated patients versus placebo-treated patients in the premarketing evaluation of Effexor XR for MDD, GAD, and SAD (see Table 6).

Effexor XR is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in Effexor XR-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Effexor XR should be considered.

5.13 Sexual Dysfunction

Use of SNRIs, including Effexor XR, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of Effexor XR and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Effexor XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole – Anaphylaxis, angioedema

Cardiovascular system – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy

Digestive system – Pancreatitis

Hemic/Lymphatic system – Mucous membrane bleeding [see Warnings and Precautions (5.4)], blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia

Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9)], Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions (5.9)], abnormal liver function tests, hepatitis, prolactin increased

Musculoskeletal – Rhabdomyolysis

Nervous system – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.2)], serotonergic syndrome [see Warnings and Precautions (5.2)], delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia

Respiratory system – Dyspnea, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions (5.12)]

Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Special senses – Angle-closure glaucoma [see Warnings and Precautions (5.5)]

7.1 Drugs Having Clinically Important Interactions with Effexor XR

7.2 Other Drug Interactions with Effexor XR

8.1 Pregnancy

8.2 Lactation

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 to17 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)].

8.5 Geriatric Use

The percentage of patients in clinical studies for Effexor XR for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 16.

No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.9)].

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [see Clinical Pharmacology (12.3)] (see Figure 1). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction [see Dosage and Administration (2.8, 2.9)].

8.6 Hepatic Impairment

Dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment or hepatic cirrhosis [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Dosage adjustment is recommended in patients with mild (CLcr= 60–89 mL/min), moderate (CLcr= 30–59 mL/min), or severe (CLcr <30 mL/min) renal impairment, and in patients undergoing hemodialysis [see Dosage and Administration (2.9) and Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Effexor XR contains venlafaxine which is not a controlled substance.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical studies. 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, providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

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

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

Discontinuation effects have been reported in patients receiving venlafaxine [see Dosage and Administration (2.10) and Warnings and Precautions (5.7)].

Human Experience

During the premarketing evaluations of Effexor XR (for MDD, GAD, SAD, and PD) and Effexor (for MDD), there were twenty reports of acute overdosage with Effexor (6 and 14 reports in Effexor XR and Effexor patients, respectively), either alone or in combination with other drugs and/or alcohol.

Somnolence was the most commonly reported symptom. Among the other reported symptoms were paresthesia of all four limbs, moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. In most cases, no signs or symptoms were associated with overdose. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. One patient who ingested 2.75 g of venlafaxine was observed to have two generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in two of the other patients.

Actions taken to treat the overdose included no treatment, hospitalization and symptomatic treatment, and hospitalization plus treatment with activated charcoal. All patients recovered.

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

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher preexisting burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Management of Overdosage

No specific antidotes for Effexor XR are known. In managing overdosage, consider the possibility of multiple drug involvement. Consider contacting a Poison Center (1-800-222-1222) or a medical toxicologist for overdosage management recommendations for Effexor XR.

12.1 Mechanism of Action

The mechanism of action of venlafaxine in the treatment of MDD, GAD, SAD, and PD is unclear, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake.

12.2 Pharmacodynamics

In-vitro studies have demonstrated that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.

12.3 Pharmacokinetics

Venlafaxine and ODV steady-state concentrations are reached within 3 days. Venlafaxine and ODV exhibited linear kinetics over the dosage range of 75 to 450 mg per day (0.33 to 2 times the maximum recommended dosage). Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

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.

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.

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.

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.

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.

Store at controlled room temperature, 20° to 25°C (68° to 77°F).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Concomitant Medication

Instruct patients not to take Effexor XR with an MAOI or within 14 days of stopping an MAOI [see Contraindications (4)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of Effexor XR with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, 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). Instruct patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Elevated Blood Pressure

Advise patients that they should have regular monitoring of blood pressure when taking Effexor XR [see Warnings and Precautions (5.3)].

Increased Risk of Bleeding

Inform patients about the concomitant use of Effexor XR with NSAIDs, aspirin, other antiplatelet drugs, warfarin, or other drugs that affect coagulation because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.4)].

Activation of Mania/Hypomania

Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.6)].

Cardiovascular/Cerebrovascular Disease

Caution is advised in administering Effexor XR to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders [see Adverse Reactions (6.1)].

Serum Cholesterol and Triglyceride Elevation

Advise patients that elevations in total cholesterol, LDL and triglycerides may occur and that measurement of serum lipids may be considered [see Adverse Reactions (6.1)].

Discontinuation Syndrome

Advise patients not to abruptly stop taking Effexor XR without talking first with their healthcare provider. Patients should be aware that discontinuation effects may occur when stopping Effexor XR and they should monitor for discontinuation symptoms [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Sexual Dysfunction

Advise patients that use of Effexor XR may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.13)].

Interference with Cognitive and Motor Performance

Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor XR therapy does not adversely affect their ability to engage in such activities.

Alcohol

Advise patients to avoid alcohol while taking Effexor XR [see Drug Interactions (7.2)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing [see Contraindications (4) and Adverse Reactions (6.2)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Effexor XR. Advise patients that Effexor XR use during mid to late pregnancy may lead to an increased risk for preeclampsia; use in late pregnancy may lead to an increased risk for postpartum hemorrhage and may increase the risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Effexor XR during pregnancy [see Use in Specific Populations (8.1)].

Residual Spheroids

Effexor XR contains spheroids, which release the drug slowly into the digestive tract. The insoluble portion of these spheroids is eliminated, and patients may notice spheroids passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the spheroids.