Efexor XR

Venlafaxine HCl.

Venlafaxine HCl is (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride.
Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent.

Pharmacology: Venlafaxine is a structurally novel antidepressant that is chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.
Mode of Action: The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, o-desmethylvenlafaxine (ODV), are potent inhibitors of serotonin and norepinephrine re-uptake. Venlafaxine also weakly inhibits dopamine re-uptake. Studies in animals show that tricyclic antidepressants may reduce β-adrenergic receptor responsiveness following chronic administration. In contrast, venlafaxine and ODV reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. The latter results may predict a more rapid onset of activity for venlafaxine. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter re-uptake.
Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H₁-histaminergic or α₁-adrenergic receptors in vitro. Pharmacologic activity at these receptors is potentially associated with various anticholinergic, sedative and cardiovascular effects seen with other psychotropic drugs.
Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
Pharmacodynamics: Clinical Efficacy: Patients With Depression: The efficacy of Efexor XR extended-release capsules as a treatment for depression was established in 2 placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM III-R or DSM-IV criteria for major depression or major depressive disorder.
A 12-week study utilizing Efexor XR doses in a range of 75-150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Efexor XR doses in a range of 75-225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Efexor XR over placebo on the HAM-D total score, HAM-D depressed mood item, the MADRS total score, the CGI severity of illness scale and the CGI global improvement scale. In both studies, Efexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization, cognitive disturbance and retardation factors, as well as the psychic anxiety score.
Depression Relapse/Recurrence: A study of depressed outpatients who had responded to Efexor XR during an initial 8-week open-label treatment phase and were randomly assigned to continuation on Efexor XR or placebo for 6 months demonstrated a significantly lower relapse rate for patients taking Efexor XR compared with those on placebo.
A study of depressed outpatients who had responded to Efexor (the immediate-release form of venlafaxine) during an initial 6-month open-label treatment phase and were randomly assigned to maintenance therapy on Efexor or placebo for 12 months demonstrated a significantly lower recurrence rate for patients taking Efexor compared with those on placebo.
Patients with Anxiety: The efficacy of Efexor XR capsules as a treatment for anxiety was established in 4 placebo-controlled studies. The studies were done in outpatients meeting DSM-IV criteria for generalized anxiety disorder, who were not depressed.
The short-term efficacy of Efexor XR was demonstrated in 4 studies. Two were 8-week studies, utilizing Efexor XR doses of 75, 150 and 225 mg/day, and of 75 and 150 mg/day, and the others were the first 8-weeks of 2 long-term studies, utilizing Efexor XR doses of 75-225 mg/day and of 37.5, 75 and 150 mg/day. Each of the 4 studies demonstrated superiority of Efexor XR over placebo on at least 5 of the following efficacy scales: The HAM-A total score, HAM-A psychic anxiety factor, hospital anxiety and depression anxiety subscale and CGI severity of illness scale, as well as the HAM-A anxious mood item and tension item.
Two of the 4 studies continued up to 6 months. These 2 studies, which utilized Efexor XR doses of 75-225 mg/day and of 37.5, 75 and 150 mg/day, demonstrated superiority of Efexor XR over placebo on the HAM-A total score, HAM-A psychic anxiety factor, HAD anxiety factor and CGI severity of illness scale, as well as the HAM-A anxious mood item.
Social Anxiety Disorder (Social Phobia): The efficacy of Efexor XR capsules as a treatment for social anxiety disorder (also known as social phobia) was established in 4 double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for social anxiety disorder. Patients received doses in a range of 75-225 mg/day. Efficacy was assessed with Liebowitz Social Anxiety Scale (LSAS). In these 5 trials, Efexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. There was no evidence for any greater effectiveness of the 150-225 mg/day group compared to the 75 mg/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 the outcome in these studies.
Panic Disorder: The efficacy of Efexor XR in the treatment of panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Efexor XR in maintaining a response in panic disorder for up to 6 months following 12 weeks of acute treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Efexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Dosage & Administration).
Pharmacokinetics: Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75-450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/hr/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hrs, respectively; and apparent (steady state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively.
Absorption: On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed, indicating that absorption of venlafaxine is nearly complete. However, the presystemic metabolism of venlafaxine (which primarily forms the active metabolite, ODV) reduces the absolute bioavailability of venlafaxine to 40-45%.
After administration of Efexor XR, the peak plasma concentrations of venlafaxine and ODV are attained within 6±1.5 and 8.8±2.2 hrs, respectively. The rate of absorption of venlafaxine from the Efexor XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of Efexor XR (15±6 hrs) is actually the absorption half-life instead of the true disposition half-life (5±2 hrs) observed following administration of an immediate-release tablet.
When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure [area under the concentration curve (AUC)] to both venlafaxine and ODV was similar for the 2 treatments and the fluctuation in plasma concentrations was slightly lower following treatment with the Efexor XR capsule. Therefore, the venlafaxine ER capsule provides a slower rate of absorption, but the same extent of absorption (ie, AUC), as the venlafaxine immediate-release tablet.
Distribution: The degree of binding of venlafaxine to human plasma proteins is 27±2% at concentrations ranging from 2.5-2215 ng/mL and the degree of ODV binding to human plasma proteins is 30±12% at concentrations ranging from 100-500 ng/mL. Protein-binding-induced drug interactions with concomitantly administered venlafaxine are not expected. Following IV administration, the steady-state volume of distribution of venlafaxine is 4.4±1.9 L/kg, indicating that venlafaxine distributes well beyond the total body water.
Metabolism: Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. The primary metabolite of venlafaxine is ODV, but venlafaxine is also metabolized to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalyzed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and extensive metabolisers. However, despite the metabolic differences between the CYP2D6 poor and extensive metabolisers, the total exposure to the sum of the 2 active species (venlafaxine and ODV) was similar in the 2 metaboliser groups. Therefore, CYP2D6 poor and extensive metabolisers can be treated with the same regimen of Efexor XR.
Excretion: Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hrs after a single radiolabeled dose as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%) or other minor inactive metabolites (27%) and 92% of the radioactive dose is recovered within 72 hrs. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.
Effects of Food: Food has no significant effect on the absorption of venlafaxine or the formation of ODV.
Age and Gender Studies: A population pharmacokinetic analysis of 404 immediate-release, venlafaxine-treated patients from 2 studies involving both twice daily and thrice daily regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences.
Patients with Hepatic Impairment: The pharmacokinetic disposition of both venlafaxine and ODV are significantly altered in some patients with compensated hepatic cirrhosis (moderate hepatic impairment) following oral administration of single-dose venlafaxine. In hepatically impaired patients, mean plasma clearance of venlafaxine and ODV are reduced approximately 30-33% and mean elimination half-lives are prolonged ≥2-fold compared to normal subjects. The reduction in both the metabolism of venlafaxine and elimination of ODV resulted in higher plasma concentrations of both venlafaxine and ODV.
In a 2nd study, venlafaxine was administered orally and IV in normal subjects (n=21) and in Child-Pugh A (n=8) and Child-Pugh B (n=11) subjects (mildly and moderately hepatically impaired, respectively). Oral bioavailability approximately doubled for hepatically impaired subjects compared to normal subjects. In hepatically impaired subjects, venlafaxine 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.
Patients with Renal Impairment: In patients with moderate to severe impairment of renal function, the total clearance of both venlafaxine and ODV was reduced, and t_½ was prolonged. The reduction in total clearance was most pronounced in subjects with creatinine clearance <30 mL/min.
Venlafaxine and ODV elimination half-lives increase with the degree of impairment in renal function. Elimination half-life increased approximately 1.5-fold in patients with moderate renal impairment and approximately 2.5- and 3-fold in patients with end-stage renal disease.
Toxicology: Preclinical Safety Data: Carcinogenicity: Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg/day, which was 1.7 times the maximum recommended human dose on a mg/m² basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg/day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended dose. Plasma levels of O-desmethylvenlafaxine were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Mutagenicity: Venlafaxine and O-desmethylvenlafaxine were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow, O-desmethylvenlafaxine was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.
Impairment of Fertility: Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human dose on a mg/kg basis, or of up to 2 times on a mg/m² basis.
Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV). This ODV exposure was approximately 2-3 times that of a human venlafaxine dose of 225 mg/day. The human relevance of this finding is unknown.
Teratogenicity: Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the human dose of venlafaxine 375 mg/day (on a mg/m² basis), or 2.5 times (rat) and 4 times (rabbit) the human dose of venlafaxine 375 mg/day (on a mg/m² basis).

Treatment of depression, including depression with associated anxiety.
Treatment of anxiety or generalized anxiety disorder, including long-term treatment.
Prevention of relapses of an episode of depression or for prevention of the recurrence of new depressive episodes.
Treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV.
Social anxiety disorder (DSM-IV) is characterized by a marked and persistent fear of ≥1 social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of Efexor XR in the treatment of social anxiety disorder was established in four 12-week and one 6-month placebo-controlled trials in outpatients with social anxiety disorder (DSM-IV) (see Pharmacodynamics: Clinical Efficacy under Actions).
Although the effectiveness of Efexor XR has been demonstrated in 6-month clinical trial in patients with social anxiety disorder, the physician who elects to use Efexor XR for extended periods should periodically re-evaluate the long-term usefulness of venlafaxine for the individual patient (see Dosage & Administration).
Treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks ie, a discrete period of intense fear or discomfort, in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 min: Palpitations, pounding heart or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded or faint; derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; fear of dying; paresthesias (numbness or tingling sensations); chills or hot flushes.

Depression: Usual Recommended Starting Dose: 75 mg given once daily.
When required, the dose can be increased in increments of up to 75 mg/day, at intervals of not less than 4 days. The dose can be titrated up to 225 mg/day in moderately depressed patients and 375 mg/day for severely depressed patients.
Antidepressant activity with the 75-mg dose was observed after 2 weeks of treatment.
Generalized Anxiety Disorder: Patients not responding to the initial 75-mg/day dose may benefit from dose increases. The dose may be stepped up (eg, by 37.5-mg increments) to a maximum of 150 mg/day or in some cases 225 mg/day. Extended-release venlafaxine dosage increases can be made at intervals of approximately ≥2 weeks, but not less than 4 days.
Anxiolytic activity with the 75-mg dose was observed after 1 week of treatment.
Social Anxiety Disorder (Social Phobia): Recommended Dose: 75 mg/day administered in a single dose. There was no evidence that higher doses confer any additional benefit.
Panic Disorder: It is recommended that initial single doses of 37.5 mg/day of Efexor XR be used for 7 days. In clinical trials establishing the efficacy of Efexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed and should be made at intervals of not less than 7 days.
Switching Patients from Efexor Tablets: Patients who are currently being treated with Efexor may be switched to Efexor XR at the nearest equivalent dose (mg/day). However, individual dosage adjustments may be necessary.
With the exception of patients with social anxiety disorder, patients not responding to the 75-mg/day dose may benefit from dose increases in increments of up to 75 mg/day to a maximum of 225 mg/day. Extended-release venlafaxine dosage increases can be made at intervals of ≥2 weeks, but not less than 4 days.
Patients with Renal Impairment: The total daily dose of venlafaxine should be reduced by 25-50% for patients with renal impairment with a glomerular filtration rate (GFR) of 10-70 mL/min.
The total daily dose of venlafaxine should be reduced by 50% in hemodialysis patients.
Because of individual variability in clearance in these patients, individualization of dosage may be desirable.
Patients with Hepatic Impairment: The total daily dose of venlafaxine should be reduced by 50% in patients with mild to moderate hepatic impairment. Reduction of >50% may be appropriate for some patients.
Because of individual variability in clearance in these patients, individualization of dosage may be desirable.
Children: There is insufficient experience with the use of venlafaxine in patients <18 years (see Use in children under Precautions and Pediatric Patients under Adverse Reactions).
Elderly: No specific dosage adjustments of venlafaxine are recommended based on patient age. As with any drug, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
Maintenance/Continuation/Extended Treatment: The physician should periodically re-evaluate the usefulness of long-term Efexor XR treatment for the individual patient. It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy.
Patients with anxiety often suffer over many years and such patients usually require long-term treatment.
Usually, the dosage for prevention of relapse or for prevention of recurrence of a new episode is similar to that used during initial treatment. Patients should be regularly re-assessed in order to evaluate the benefit of long-term therapy.
Efexor was shown to be efficacious during long-term treatment (up to 12 months in depression and up to 6 months in anxiety).
Discontinuing Efexor XR: Dose tapering is recommended when discontinuing venlafaxine therapy (see Precautions and Adverse Reactions). In clinical trials with venlafaxine extended-release capsule, tapering was achieved by reducing the daily dose by 75 mg at 1-week intervals. The period required for tapering may depend on the dose, duration of therapy and the individual patient.
Administration: It is recommended that Efexor XR be taken with food. Each capsule should be swallowed whole with fluid. Do not divide, crush, chew or dissolve. Efexor XR should be administered once daily at approximately the same time either in the morning or in the evening.

In animal toxicology studies, the oral LD₅₀ values for venlafaxine were equivalent to 45-90 times the maximum recommended human dose.
Among the patients treated with Efexor XR in premarketing depression evaluations, there were 2 reports of acute overdosage, either alone or in combination with other drugs. One patient took a combination of Efexor XR 6 g and lorazepam 2.5 mg. This patient was hospitalized, treated symptomatically and recovered without any untoward effects. The other patient took Efexor XR 2.85 g. This patient reported paresthesia of all 4 limbs but recovered without sequelae.
There were 2 reports of acute overdose with Efexor XR in anxiety trials. One patient took a combination of Efexor XR 0.75 g, paroxetine 200 mg and zolpidem 50 mg. This patient was described as being alert, able to communicate and a little sleepy. This patient was hospitalized, treated with activated charcoal and recovered without any untoward effects. The other patient took Efexor XR 1.2 g. This patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. The patient recovered and no other specific problems were found.
Among the patients treated with Efexor in premarketing evaluations, there were 14 reports of acute overdose, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of Efexor 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, 2.75 and 2.5 g. All 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 Efexor was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Coma resulted and resuscitation was required. Mild sinus tachycardia was reported in 2 of the other patients.
In post-marketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion and vomiting. Other changes reported include electrocardiographic changes (eg, prolongation of QT interval, bundle-branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, vertigo and death.
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 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 characteristics of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of drug consistent with good patient management, in order to reduce the risk of overdose.
Treament: General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients.
Administration of activated charcoal may also limit drug absorption.
Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for venlafaxine are known.

Hypersensitivity to venlafaxine or any excipients of Efexor XR.
Concomitant use of venlafaxine and any monoamine oxidase inhibitor (MAOI). Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with a MAOI; a shorter interval may be justified in the case of a reversible MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with any MAOI (see Interactions).

All patients treated with venlafaxine should be monitored appropriately and observed closely for clinical worsening and suicidality. Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen.
The risk of suicide attempt must be considered especially in depressed patients and the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose. (See Use in children under Precautions and Pediatric Patients under Adverse Reactions.)
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are strong predictors of suicide. Pooled analyses of short-term placebo-controlled trials of antidepressant medicines (SSRIs and others) showed that these medicines increase the risk of suicidality in children, adolescents and young adults (18-24 years) with major depression and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults >24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults ≥65 years.
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition may occur with venlafaxine treatment particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter systems (see Interactions).
Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.

Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.
Dose-related increases in blood pressure have been reported in some patients treated with venlafaxine. Cases of elevated blood pressure requiring immediate treatment have been reported in post-marketing experience. Measurement of blood pressure is recommended for patients receiving venlafaxine. Preexisting hypertension should be controlled before treatment with venlafaxine. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure.
Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.
Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be introduced with caution in patients with a history of convulsions.
Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.
Aggression may occur in a small proportion of patients who have received antidepressants, including venlafaxine treatment, dose reduction or discontinuation.
As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.
Cases of hyponatremia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion may occur with venlafaxine, usually in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics and patients who are otherwise volume depleted, may be at a greater risk for this event.
Drugs that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. The risk of skin and mucous membrane bleeding, including gastrointestinal hemorrhage, may be increased in patients taking venlafaxine. As with other serotonin re-uptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors.
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine HCl and weight loss agents is not recommended. Venlafaxine HCl is not indicated for weight loss alone or in combination with other products.
Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.
Discontinuation effects are well-known to occur with antidepressants, and it is therefore recommended that the dosage of either formulation of venlafaxine be tapered gradually and the patient monitored. (See Dosage & Administration and Adverse Reactions.)
Abuse and Dependence: Clinical studies did not show evidence of drug-seeking behavior, development of tolerance or dose escalation over time.
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. However, physicians should evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Efexor XR eg, development of tolerance, dose escalation or drug-seeking behavior.
Effects on the Ability to Drive or Operate Machinery: Venlafaxine did not affect psychomotor, cognitive or complex behavior performance in healthy volunteers. However, any psychoactive drug may impair judgment, thinking and motor skills. Therefore, patients should be cautioned about their ability to drive or operate hazardous machinery.
Use in Pregnancy: The safety of venlafaxine in human pregnancy has not been established. Venlafaxine must be administered to pregnant women only if the expected benefits outweigh the possible risks. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered. Some neonates exposed to venlafaxine late in the 3rd trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalization. Such complications can arise immediately upon delivery.
Use in Lactation: Venlafaxine and ODV are excreted in human milk; therefore, a decision should be made whether not to breastfeed or to discontinue venlafaxine.
Use in Children: Efficacy in patients <18 years has not been established.
In pediatric clinical trials, the adverse reaction, suicidal ideation, was observed. There were also increased reports of hostility and especially in major depressive disorder, self-harm.
As with adults, decreased appetite, weight loss, increased blood pressure and increased serum cholesterol have been observed in children and adolescents (6-17 years; see Adverse Reactions). Regular measurement of weight and blood pressure is recommended if venlafaxine is used in children and adolescents. Discontinuation of venlafaxine treatment should be considered for children and adolescents who experience a sustained increase in blood pressure. Measurement of serum cholesterol levels should be considered during long-term treatment of children and adolescents (see Dosage & Administration and Adverse Reactions). Safety in children <6 years has not been evaluated.
Use in the Elderly: No specific dosage adjustments of venlafaxine are recommended based on patient age.

Use in Pregnancy: The safety of venlafaxine in human pregnancy has not been established. Venlafaxine must be administered to pregnant women only if the expected benefits outweigh the possible risks. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered. Some neonates exposed to venlafaxine late in the 3rd trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalization. Such complications can arise immediately upon delivery.
Use in Lactation: Venlafaxine and ODV are excreted in human milk; therefore, a decision should be made whether not to breastfeed or to discontinue venlafaxine.

Adverse reactions are listed as follows in CIOMS frequency categories. Common: ≥1%; uncommon: ≥0.1% and <1%; rare: ≥0.01% and <0.1%; very rare: <0.01%.
Body as a Whole: Common: Asthenia/fatigue, chills. Uncommon: Angioedema, photosensitivity reaction. Very Rare: Anaphylaxis.
Cardiovascular: Common: Hypertension, vasodilatation (mostly hot flushes/flashes), palpitations. Uncommon: Hypotension, postural hypotension, syncope, tachycardia. Very Rare: QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes).
Digestive: Common: Decreased appetite, constipation, nausea, vomiting. Uncommon: Bruxism, diarrhea. Very Rare: Pancreatitis.
Hematological/Lymphatic: Uncommon: Ecchymosis, mucous membrane bleeding, gastrointestinal hemorrhage. Rare: Prolonged bleeding time, thrombocytopenia. Very Rare: Blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia).
Metabolic/Nutritional: Common: Increased serum cholesterol (particularly with prolonged administration and possibly with higher doses), weight loss. Uncommon: Abnormal liver function tests, hyponatremia, weight gain. Rare: Hepatitis, SIADH. Very Rare: Increased prolactin.
Musculoskeletal: Very Rare: Rhabdomyolysis.
Nervous: Very Common: Headache. Common: Abnormal dreams, decreased libido, dizziness, dry mouth, increased muscle tonus, insomnia, nervousness, paresthesia, sedation, tremor, confusion, depersonalization. Uncommon: Apathy, hallucinations, myoclonus, agitation, impaired coordination and balance. Rare: Akathisia/psychomotor restlessness, convulsion, manic reaction, neuroleptic malignant syndrome (NMS), serotonergic syndrome. Very Rare: Delirium, extrapyramidal reactions (including dystonia and dyskinesia), tardive dyskinesia.
Respiratory: Common: Yawning. Very Rare: Pulmonary eosinophilia.
Skin: Common: Sweating (including night sweats). Uncommon: Rash, alopecia. Very Rare: Erythema multiforme, Stevens-Johnson syndrome, pruritus, urticaria. Frequency Unknown: Toxic epidermal necrolysis.
Special Senses: Common: Abnormality of accommodation, mydriasis, visual disturbance. Uncommon: Altered taste sensation, tinnitus. Very Rare: Angle-closure glaucoma.
Urogenital: Common: Abnormal ejaculation/orgasm (males), anorgasmia, erectile dysfunction, impaired urination (mostly hesitancy), menstrual disorders associated with increased bleeding or increased irregular bleeding (eg, menorrhagia, metrorrhagia), increased urinary frequency. Uncommon: Abnormal orgasm (females), urinary retention. Rare: Urinary incontinence.
The following symptoms have been reported in association with abrupt discontinuation or dose reduction or tapering of treatment: Hypomania, anxiety, agitation, nervousness, confusion, insomnia or other sleep disturbances, fatigue, somnolence, paresthesia, dizziness, convulsion, vertigo, headache, flu-like symptoms, tinnitus, impaired coordination and balance, tremor, sweating, dry mouth, anorexia, diarrhea, nausea and vomiting. In premarketing studies, the majority of discontinuation reactions were mild and resolved without treatment.
Pediatric Patients: In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (6-17 years) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure and increased serum cholesterol were observed (see Use in children under Precautions).
In pediatric clinical trials, the adverse reaction, suicidal ideation, was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm. Particularly, the following adverse reactions were observed in pediatric patients: Abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis and myalgia.

MAOI: Severe adverse reactions have been reported in patients who have recently been discontinued from a MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of a MAOI (see Contraindications). These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness and hyperthermia with features resembling NMS, seizures and death.
CNS-Active Drugs: The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination with other CNS-active drugs.
Serotonin Syndrome: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system [including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol or St. John's wort (Hypericum perforatum)], with drugs which impair metabolism of serotonin [eg, MAOIs, including linezolid, an antibiotic which is a reversible nonselective MAOI (see Contraindications)] or with serotonin precursors (eg, tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms. (See Contraindications and Warnings.)
If concomitant treatment of venlafaxine with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (eg, tryptophan supplements) is not recommended (see Warnings). Indinavir: A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this interaction is unknown.
Ethanol: Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS active drugs, patients should be advised to avoid alcohol consumption while taking venlafaxine.
Haloperidol: A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, 70% increase in AUC and 88% increase in C_max, but no change in half-life. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly.
Cimetidine: At steady state, cimetidine has been shown to inhibit first-pass metabolism of venlafaxine; however, cimetidine had no effect on the pharmacokinetics of ODV. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly in most patients. For elderly patients or in patients with hepatic dysfunction, this interaction could potentially be more pronounced and for such patients, clinical monitoring is indicated when Efexor XR is administered with cimetidine.
Imipramine: Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C_max and C_min increased by about 35% in the presence of venlafaxine. There was an increase of 2-OH-desipramine AUC by 2.5- to 4.5-fold. Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. This should be taken into account in patients treated with imipramine and venlafaxine concomitantly.
Ketoconazole: A pharmacokinetic study with ketoconazole in extensive (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in subjects following administration of ketoconazole. Venlafaxine C_max increased by 26% in EM subjects and 48% in PM subjects. C_max values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects. AUC values for ODV increased by 23% and 33% in EM and PM subjects, respectively (see Potential for Other drugs to Affect Venlafaxine as follows).
Metoprolol: Concomitant administration of venlafaxine (50 mg every 8 hrs for 5 days) and metoprolol (100 mg every 24 hrs for 5 days) to healthy volunteers in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Venlafaxine appeared to reduce the blood pressure-lowering effect of metoprolol in this study of healthy volunteers. The clinical relevance of this finding is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, ODV. Caution should be exercised with co-administration of venlafaxine and metoprolol.
Risperidone: Venlafaxine increased the risperidone AUC by 32% but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Diazepam: Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or ODV. Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam.
Lithium: The steady-state pharmacokinetics of venlafaxine and ODV are not affected when lithium is co-administered. Venlafaxine also has no effect on the pharmacokinetics of lithium. (See previous text on CNS-Active Drugs).
Drugs Highly Bound to Plasma Proteins: Venlafaxine is not highly bound to plasma proteins (27% bound), therefore, administration of venlafaxine to a patient taking another drug that is highly protein bound is not expected to cause increased free concentrations of the other drug.
Drugs Metabolised by Cytochrome P-450 Isoenzymes: Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP3A4, CYP1A2 and CYP2C9 in vitro. This was confirmed by in vivo studies with the following drugs: Alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine (CYP3A4), diazepam (CYP3A4 and CYP2C19) and tolbutamide (CYP2C9).
Potential for Other Drugs to Affect Venlafaxine: The metabolic pathways for venlafaxine include CYP2D6 and CYP3A4. Venlafaxine is primarily metabolised to its active metabolite, ODV, by the cytochrome P-450 enzyme CYP2D6. CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine.
CYP2D6 Inhibitors: Concomitant use of CYP2D6 inhibitors and venlafaxine may reduce the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of ODV. As venlafaxine and ODV are both pharmacologically active, no dosage adjustment is required when venlafaxine is co-administered with a CYP2D6 inhibitor.
CYP3A4 Inhibitors: Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV (see previous text on Ketoconazole). Therefore, caution is advised when combining venlafaxine with a CYP3A4 inhibitor.
CYP2D6 and 3A4 Inhibitors: The concomitant use of venlafaxine with drug treatment(s) that potentially inhibit both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. However, this concomitant use would be expected to increase venlafaxine plasma concentrations. Therefore, caution is advised when combining venlafaxine with any agent(s) that produce simultaneous inhibition of these 2 enzyme systems.
Electroconvulsive Therapy: There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine treatment.

Antidepressants

N06AX16 - venlafaxine ; Belongs to the class of other antidepressants.

D