Venlafaxine (Systemic)


VA CLASSIFICATION
Venlafaxine
Primary: CN609
Secondary: CN304


Commonly used brand name(s): Effexor; Effexor XR.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidepressant—

Antianxiety agent—

Indications

Accepted

Depressive disorder, major (treatment)—Venlafaxine is indicated for the treatment of major depressive disorder {01} {02} {03} {08} {09} {10} {15} {17}. Treatment of acute depressive episodes typically requires 6 to 12 months of antidepressant therapy {22}. Patients with recurrent or chronic depression may require long-term treatment {22}.

Anxiety (treatment)—The extended-release dosage form of venlafaxine is indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. However, venlafaxine usually is not indicated for the treatment of anxiety or tension associated with the stress of everyday life.
{40}
[Hot flashes (treatment)]1—Venlafaxine is indicated for the treatment of hot flashes.{41}{42}{43}{44}{45}{46}{47}{48}{49} A double-blind, placebo-controlled trial, conducted in 229 women, demonstrated a 58% reduction in hot flash frequency and 61% reduction in hot flash score.{42}{43} Women included in the study had a history of breast cancer or refused to use hormonal therapy due to fear of developing breast cancer. Additionally, two smaller open-label trials, enrolling women with a history of breast cancer or men with androgen deprivation therapy, also reported reduction in hot flash frequency with venlafaxine.{44}{48}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: A large degree of interpatient variability has been observed in the pharmacokinetic parameters of venlafaxine in patients with hepatic or renal function impairment {01} {03} {06}.


Physicochemical characteristics:
    Chemically unrelated to tricyclic, tetracyclic, or other currently available antidepressants and to other drugs used to treat anxiety disorders{01} {02} {03}.

Chemical group—
    Phenethylamine {04} {05} {24} {25}.
Molecular weight—
    Venlafaxine hydrochloride: 313.87 {21}
    Venlafaxine: 277 {12}
    O-desmethylvenlafaxine (ODV): 263 {12}

pKa—
    9.4 {02} {24}

Mechanism of action/Effect:

The antidepressant action of venlafaxine is believed to be associated with its ability to potentiate neurotransmitter activity in the central nervous system (CNS) {01} {02} {03}. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin (5-hydroxytryptamine; 5-HT) {01} {02} {03} {16} {20} {26} reuptake, slightly less potent inhibitors of neuronal norepinephrine {04} {14} {25} reuptake, and weak inhibitors of neuronal dopamine reuptake {01} {02} {03} {16} {20} {25}. Venlafaxine inhibits serotonin reuptake less potently than do the selective serotonin reuptake inhibitors {04} {24}. Studies in rats indicate that venlafaxine induces reduced sensitivity of the adenylate-cyclase coupled beta-adrenergic system after single doses {04}. Many other currently available antidepressants induce this change in beta-receptor sensitivity only after repeated dosing {04}. However, not all antidepressants produce beta-adrenergic subsensitivity {04}, and the clinical significance of this effect remains to be determined {29}.

Neither venlafaxine nor ODV has demonstrated specific affinity for adrenergic alpha 1 receptors {01} {02} {03} {13} {14} {24}, muscarinic receptors {01} {02} {03} {13} {14} {16} {24} {25} {26}, or histaminergic H 1 receptors {01} {02} {03} {04} {05} {13} {14} {24} {25} {26}. Venlafaxine has demonstrated no specific affinity for adrenergic {04} {05} {16} {25} alpha 2 {14} {24} or beta {04} {14} {16} {24} receptors, dopaminergic D 2 receptors {14} {16}, serotonergic {05} {16} 5HT 1 or 5HT 2 {04} {14} receptors, benzodiazepine receptors {01} {03} {04} {14} {16} {24}, opiate receptors {02} {04} {10} {13} {14} {16} {24}, phencyclidine (PCP) receptors {01} {02} {03} {24}, or N-methyl-D-aspartic acid (NMDA) receptors {01} {02} {03} {24} in vitro {02} {14} {16}. Neither venlafaxine nor ODV inhibits monoamine oxidase {01} {02} {03} {13} {14} {16} {24} {26}.


Other actions/effects:

The immediate-release form of venlafaxine induces hypertension in a dose-related manner at an incidence ranging from 3 to 7% (at doses between 100 and 300 mg per day) to 13% (at doses above 300 mg per day) {40}. The extended-release form of venlafaxine induces hypertension in 0.4% and 3% of patients treated for generalized anxiety disorder and depression, respectively{40}.

Absorption:

Venlafaxine is rapidly {04} {14} {20} {24} and well absorbed {01} {02} {03}. At least 92% of a single dose is absorbed, based on mass balance studies {01} {03}. The bioavailability of venlafaxine is the same with a tablet or with an oral solution {01} {03} and is about 45% {01}. Food delays absorption {10} {17} {20}, but does not impair extent of absorption {04} {10} {17} of venlafaxine.

Venlafaxine release from the extended-release dosage form is membrane-controlled and is not pH-dependent {01}. Although absorption from the extended-release dosage form occurs at a slower rate and results in a lower maximum plasma concentration of venlafaxine, the extent of absorption is the same as with the prompt-release tablet {01}.

Distribution:

Venlafaxine Vol D—7.5 ± 3.7 L per kg of body weight (L/kg) {01} {03}.

ODV Vol D—5.7 ± 1.8 L/kg {01} {03}.

Venlafaxine is distributed into breast milk{40}.

Protein binding:

Low to moderate.

Venlafaxine—25 to 30% {01} {10} {13} {24} {25}.

ODV—18 to 42% {01} {24}.

Biotransformation:

Venlafaxine is extensively metabolized in the liver {01} {03} {09} {24} and undergoes significant first-pass metabolism {04} {13} {20} {25}. The primary metabolite is O-desmethylvenlafaxine (ODV) {01} {02} {04} {12} {13} {16}, which is approximately equivalent in pharmacologic activity and potency to venlafaxine {01}. ODV is formed by O-demethylation {09} {12} {17} via the cytochrome P450 2D6 (CYP2D6) isoenzyme {01} {02} {03} {25}. Biotransformation of venlafaxine to ODV is saturable to a modest degree {13}. In vitro studies indicate that the CYP3A4 isoenzyme is involved in the metabolism of venlafaxine to a minor, less active metabolite than ODV, N-desmethylvenlafaxine {03}.

In nine patients with cirrhosis, hepatic clearance of venlafaxine was decreased by about 50% {01} {02} {24}, and that of ODV was decreased by about 30% {01} {02} {24}. Clearance of venlafaxine in three patients with more severe cirrhosis was decreased by about 90% {01} {02}.

Half-life:


Elimination:

Venlafaxine: 5 ± 2 hours {01} {03}.

ODV: 11 ± 2 hours {01} {03}.

In nine patients with cirrhosis, elimination half-lives were increased by about 30% for venlafaxine, and by about 60% for ODV {01} {02} {03} {24}.

In patients with renal function impairment, elimination half-lives were increased by about 50% for venlafaxine {02} {03} {06}, and by about 40% for ODV {02} {03}. In dialysis patients, venlafaxine elimination half-life was increased by up to 1.5 times that of patients with normal renal function {06}.


Onset of action:

Although some symptoms of major depression may improve within about 2 weeks {02} {04} {05}, significant overall improvement may take several weeks {02} {04}.

Time to peak concentration:


Prompt-release dosage form:

Venlafaxine: Approximately 2 hours {02} {04} {10} {14} {20} {24}.

ODV: 3 to 4 hours {01} {02}.



Extended-release dosage form:

Venlafaxine: Approximately 5.5 hours {01}.

ODV: Approximately 9 hours {01}.


Peak plasma concentration

Mean peak plasma concentrations (C max) following administration of 25, 75, or 150 mg of the prompt-release dosage form of venlafaxine to 18 healthy males every 8 hours for three days were 53, 167, and 393 nanograms/mL (0.19, 0.603, and 1.42 micromoles/L), respectively, for venlafaxine, and 148, 397, and 686 nanograms/mL (0.563, 1.51, and 2.61 micromoles/L), respectively, for ODV {13}. C max is generally lower following administration of the extended-release dosage form {01}. Both venlafaxine and ODV exhibit linear pharmacokinetics over the dose range of 75 to 450 mg of venlafaxine per day {01} {02} {10}.

Steady-state concentrations of venlafaxine and ODV are attained within 3 days with regular oral dosing {01} {03}.

Elimination:


Renal—
        Approximately 87% of a dose is recovered in the urine within 48 hours {01} {02} {06} {12}, with unchanged venlafaxine comprising about 5% {01} {02} {06} {12}, unconjugated ODV comprising about 29% {01} {02} {06} {12} {13}, conjugated ODV comprising about 26% {01} {02}, and other minor inactive metabolites comprising about 27% {01} {02} of the amount excreted.
        In patients with renal function impairment, the clearance of venlafaxine was decreased by about 24%, but the clearance of ODV was unchanged {01} {02}. In patients with end-stage renal disease, total clearance of venlafaxine and ODV was decreased by about 55% {06} {24}.
        In dialysis: In one study of six patients on maintenance hemodialysis, a 4-hour dialysis treatment removed only about 5% of a single 50-mg dose of venlafaxine {06} {24}.



Fecal—
        Approximately 2% of a dose of venlafaxine is recovered in feces after 35 days {12}.



Precautions to Consider

Carcinogenicity/Tumorigenicity

Studies in rats and mice that received venlafaxine for 24 and 18 months, respectively, have shown no evidence of an increased risk of tumor development {01} {02}.

Mutagenicity

Venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in a battery of in vivo and in vitro tests {01} {03}. However, there was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow {01} {03} in male rats receiving 200 times, on a mg per kg of body weight (mg/kg) basis, or 50 times, on a mg per square meter of body surface area (mg/m 2) basis, the maximum recommended human dose (MRHD) of venlafaxine {03}. The no-effect dose was 67 times (mg/kg) or 17 times (mg/m 2) the MRHD {03}.

Pregnancy/Reproduction
Fertility—
No effects on male or female fertility were reported in rats administered oral doses of up to eight times the MRHD of venlafaxine on a mg/kg basis, or up to two times the MRHD on a mg/m 2 basis {01} {03}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01} {24}.

No teratogenic effects were observed in rats or rabbits given the MRHD of venlafaxine on a mg/kg basis {01} (2.5 or 4 times, respectively, the MRHD on a mg/m 2 basis {01} {03}). However, when dosing in rats began during pregnancy and continued until weaning, a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation occurred {01} {03}. The cause of these deaths is not known {01} {03}.

FDA Pregnancy Category C {01} {03}.


Labor and delivery—

The effect of venlafaxine on labor and delivery in humans is unknown {01} {03}.

Breast-feeding

Venlafaxine and ODV are distributed into breast milk{40} and may cause unwanted effects in the nursing infant.

Pediatrics

No information is available on the relationship of age to the effects of venlafaxine in pediatric patients. Safety and efficacy in children up to 18 years of age have not been established {02} {03}{40}.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of venlafaxine in the elderly. However, elderly patients are more likely to have age-related renal or hepatic impairment, which may require a dose reduction in patients receiving venlafaxine{40}


Pharmacogenetics

Subjects with low cytochrome P450 2D6 (CYP2D6) activity, known as poor metabolizers, showed decreased ODV and increased venlafaxine concentrations as compared with concentrations in subjects with normal CYP2D6 activity, known as extensive metabolizers {01} {03}. However, since the sums of the concentrations of ODV and venlafaxine in the two groups were similar, this difference in metabolism is not likely to be of clinical significance {01} {03}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Possible interactions with medications that inhibit cytochrome P450 2D6 (CYP2D6) metabolism potentially may result in increased plasma concentrations of venlafaxine {01} {03} and decreased plasma concentrations of O-desmethylvenlafaxine (ODV) {01}. However, the sum of the venlafaxine and ODV concentrations is not expected to change significantly, and dosage adjustments are not recommended {01} {03}.
CYP3A4 is involved to a lesser extent in the metabolism of venlafaxine and the effects of concomitant use of venlafaxine and a potent inhibitor of both CYP2D6 and CYP3A4 on venlafaxine pharmacokinetics are unknown {01} {03}.
In vivo and in vitro studies indicate that venlafaxine weakly inhibits CYP2D6 but does not inhibit CYP1A2, CYP2C9, CYP2C19, or CYP3A4 {01} {03}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol {01} or
CNS depression–producing medications (see Appendix II )    (although venlafaxine has not been shown to increase impairment of mental and motor skills {01} {10} {25}, concomitant use with alcohol in depressed patients is not recommended {01} {03})

    (similarly, CNS depressants should be administered with caution {01} {02} {03}, since the potential for interactions in clinical practice is not known {02} {03})


Cimetidine {01} {02} {24}    (in 18 healthy subjects, cimetidine inhibited the first-pass metabolism of venlafaxine, resulting in a decrease in clearance of about 43% and an increase in maximum plasma concentrations of about 60%; however, there was no apparent effect on the pharmacokinetics of ODV, which was present in the circulation in much greater quantities; thus, the overall pharmacologic activity of venlafaxine plus ODV was only slightly increased; dosage adjustments are not needed for most patients {01} {02} {03})

    (this interaction potentially could be more pronounced in the elderly {01} {03}, in patients with pre-existing hypertension {01} {03} {24}, or in patients with hepatic {01} {03}; caution should be exercised when venlafaxine and cimetidine are used concurrently in these patients {01} {02} {03})


Haloperidol    (the area under the plasma concentration–time curve [AUC] of haloperidol was increased by 70%, the maximum plasma concentration [C max] was increased by 88%, the oral-dose clearance [Cl/F] was decreased by 42%, and the half-life was unchanged when a single 2-mg dose of haloperidol was administered to 24 healthy subjects who were at steady-state on a venlafaxine dosage of 150 mg per day {01} {03} administered as 75 mg every 12 hours {03})


» Moclobemide    (because of the potentially fatal consequences of combining non-selective, irreversible monoamine oxidase inhibitors with venlafaxine, and the increased risk of developing the serotonin syndrome with combined use of venlafaxine and the reversible monoamine oxidase-A inhibitor moclobemide, concurrent use is not recommended and a wash-out period of 3 to 7 days is advised between the use of one medication and the other {38})


» Monoamine oxidase (MAO) inhibitors {01} {02} {03} {23} , including furazolidone, procarbazine, and selegiline    (concurrent use of MAO inhibitors with venlafaxine may result in confusion, agitation, restlessness, and gastrointestinal symptoms, or possibly hyperpyretic episodes, severe convulsions, hypertensive crises, or the serotonin syndrome; concurrent use of an MAO inhibitor with venlafaxine is contraindicated {01} {03}; at least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of venlafaxine {01} {03} {23}; at least 7 days should elapse between discontinuation of venlafaxine and initiation of an MAO inhibitor {01} {03} {23})


» Serotonergics or other medications or substances with serotonergic activity (see Appendix II )    (increased risk of development of the serotonin syndrome, a rare but potentially fatal hyperserotonergic state which may occur in patients receiving serotonergic medications, usually in combination; symptoms typically occur shortly [hours to days] after the addition of a serotonergic agent to a regimen that includes serotonin-enhancing drugs; symptoms include agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes [confusion, hypomania], myoclonus, shivering, or tremor; effects including cardiac arryhthmias, coma, disseminated intravascular coagulation, hyper- or hypo-tension, renal failure, respiratory failure, seizures, and severe hyperthermia have been reported also {36})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood pressure    (dose-related sustained hypertension, defined as supine diastolic blood pressure measurements on three consecutive visits that are ³ 90 mm Hg and that are increased over baseline by ³ 10 mm Hg, has been reported {01} {03})


Cholesterol, serum    (mean increases in serum cholesterol concentrations of 3 mg/dL from baseline have been reported {03}; the clinical significance of this finding is not known {01} {02})


Electrocardiogram (ECG)    (mean change in corrected QT interval [QT c] in 357 patients receiving the extended-release dosage form of venlafaxine was an increase of 4.7 milliseconds [msec] as opposed to a 1.9 msec decrease in 285 placebo-treated patients {01})


Pulse    (heart rate increases of three to nine beats per minute have been reported {09}, with a mean increase of four beats per minute {01} {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Blood pressure problems {02} {24} or
» Cardiac disease {02}    (sustained hypertension or orthostatic hypotension induced by venlafaxine may exacerbate these conditions {02})


» Hepatic function impairment    (metabolism of venlafaxine may be altered; large interindividual variation in venlafaxine clearance is seen in these patients; patients with moderate to severe impairment may require dosage reductions of 50% or more {01} {02} {03} {06})


» Mania, history of    (activation of hypomania or mania has been reported in depressed patients treated with venlafaxine {01} {03})


Neurological impairment, including mental retardation    (risk of seizures may be increased {22})


» Renal function impairment    (excretion of venlafaxine may be altered; large interindividual variation in venlafaxine clearance is seen in these patients; patients with mild to moderate impairment may require dosage reductions of 25 to 50%; patients undergoing hemodialysis should receive a dosage reduction of 50% and the dose should be administered after the dialysis session is completed {01} {02} {03})


Seizures, history of    (as with other antidepressants, venlafaxine should be introduced with caution; if seizures develop, venlafaxine should be discontinued {01} {03})


Sensitivity to venlafaxine {02}
Weight loss    (loss of ³ 5% of baseline body weight occurred in 6% of patients receiving venlafaxine in clinical trials and in 1% of patients receiving placebo; significant weight loss, if it occurs, may be undesirable in some patients {03})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure measurements    (recommended at regular intervals because of sustained increases in blood pressure associated with venlafaxine treatment; dosage reduction or discontinuation of venlafaxine treatment should be considered in patients who develop sustained increases in blood pressure {01} {02} {03})


Careful supervision of depressed patients with suicidal tendencies     (recommended especially during early treatment phase before peak effectiveness of venlafaxine is achieved; prescribing the smallest number of tablets necessary for good patient management is recommended to decrease the risk of overdose {01} {02} {03})




Side/Adverse Effects

Note: Venlafaxine is generally well-tolerated {07} {09} {10} {11} {15} {17} {20} {26}, with evidence of dose-dependency for some of the most common adverse effects {01}. In addition, there is evidence of adaptation with continuing therapy to some effects such as nausea {02} {07} {11} {18}, vomiting {13}, somnolence {05}, and dizziness {02} {05} {13}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Headache {01} {02} {03} {08} {11} {15}
    
hypertension {01} {02} {03} {26} (high blood pressure)—usually asymptomatic
    
sexual dysfunction, including anorgasmia
decreased libido
delayed ejaculation
or impotence {01}{02}{03}{11}{18}(decrease in sexual drive or performance)
    
vision disturbances, including abnormal accommodation {01} {02} {19}
and blurred vision {01} {02} {04} {08}

Note: Sexual dysfunction may be dose-related {02} {03} {11} and does not show evidence of adaptation with continuing venlafaxine therapy {03}.
Venlafaxine-induced sustained hypertension, defined as supine diastolic blood pressure measurements on three consecutive visits that are ³ 90 mm Hg and that are increased over baseline by ³ 10 mm Hg, is reported to be dose-dependent {01} {02} {03} {04} {20}.
Probability of Sustained Hypertension*

Venlafaxine Dose (mg/day)
Incidence (%)
< 100
3
101 to 200
5
201 to 300
7
> 300
13
Placebo
2
* Estimated by the manufacturer from pooled data of premarketing studies of the prompt-release dosage form {02} {03}.



Incidence less frequent
    
Cardiovascular effects, other, including chest pain {01} {02} {03}
palpitation {07} {15} ( fast or irregular heartbeat), and tachycardia {01} {02} {07} {26} (fast heartbeat)
    
CNS effects (mood or mental changes), including abnormal thinking {01} {02} {03}
agitation {01} {02} {03} {09}
confusion {01} {02} {03}
depersonalization {01} {02} {03}
and emotional lability {01} {02} {03}
    
tinnitus {01} {02} {03} (ringing or buzzing in ears )

Incidence rare
    
Dyspnea {01} {02} {03} (trouble in breathing)
    
edema {01} {02} {03} ( swelling)
    
itching {01} {02} {03} or skin rash {01} {02} {03} {05}
    
mania or hypomania {01} {02} {03} {05} ( talking, feeling, and acting with excitement and activity one cannot control )
    
menstrual changes {01} {02} {03}
    
orthostatic hypotension {01} {02} {03} {07} ( lightheadedness or fainting)— especially when getting up suddenly from a sitting or lying position
    
seizures {01} {02} {03} {05} {08} (convulsions)
    
trismus {01} {02} (lockjaw)
    
urinary effects, including impaired urination {01} {02} {03}
urinary frequency {01} {02} {03}
urinary incontinence {30}
or urinary retention {01} {02} {03} {08} (problems in urinating or in holding urine)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abnormal dreams {01} {02} {03}
    
anorexia {01} {02} {03} {09} {20} (loss of appetite)
    
anxiety {02} {03} {08} {11} {15} or nervousness {01} {02} {03} {10} {11} {17} {18}
    
asthenia {01} {02} {03} {10} {11} (unusual tiredness or weakness)
    
chills {01} {02} {03}
    
constipation {01} {02} {03} {07} {08} {09} {10} {11} {15}
    
diarrhea {01} {02} {03} {07}
    
dizziness {01} {02} {03} {09} {10} {11}
    
dryness of mouth {01} {02} {03} {07} {08} {09} {10} {11}
    
dyspepsia {02} {03} (heartburn)
    
increased sweating {01} {02} {03} {09} {10} {11} {17}
    
insomnia {01} {02} {03} {08} {09} {10} {11} {15} (trouble in sleeping)
    
nausea {01} {02} {03} {07} {08} {09} {10} {11} {15} {17} {18} {20}
    
paresthesia {01} {02} (tingling, burning, or prickly sensations)
    
rhinitis {09} {27} (stuffy or runny nose)
    
somnolence {01} {02} {03} {09} {11} {15} {18} {19} (drowsiness)
    
stomach pain or gas {01} {02} {03} {19}
    
tremor {01} {02} {03} (trembling or shaking)
    
vomiting {01} {02} {03} {07} {13} {20}
    
weight loss {01} {03} {09}
yawning{01}{02}

Note: Anorexia, chills, dizziness, nausea, somnolence, sweating, tremor, vomiting, and weight loss may be dose-related {02} {03} {11} {15} {17} {20}. Loss of ³ 5% of baseline body weight occurred in 6% of patients in clinical trials of venlafaxine {03}.


Incidence less frequent
    
Hypertonia {01} {03} (muscle tension )
    
taste perversion {01} {02} {03} (change in sense of taste)
    
{01} {02}



Those indicating the need for medical attention if they occur after medication is discontinued
    
Asthenia{01} {02} {03} {24} (unusual tiredness or weakness)
    
changes in dreaming {31}
    
dizziness {01} {02} {03} {24} {31}
    
dryness of mouth {01}
    
headache {02} {03} {24}
    
increased sweating {01}
    
insomnia {01} {02} {03} {24} (trouble in sleeping)
    
nausea {01} {02} {03} {24}
    
nervousness {01} {02} {03} {24}




Overdose
For specific information on the agents used in the management of venlafaxine overdose, see Charcoal, Activated (Oral-Local) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)–not necessarily inclusive:
    
Agitation {32}
    
electrocardiogram (ECG) changes, specifically QT c prolongation {01} {03}
    
lethargy {05} {32} (extreme tiredness or weakness)
    
paresthesia {01} (tingling, burning, or prickling sensations)
    
seizures {01} {02} {03} {32} {33}
    
sinus tachycardia {01} {02} {03} {32} (fast heartbeat )
    
somnolence {01} {02} {03} {32} (drowsiness)
    
tremor {32} (trembling or shaking)

Note: Only a small number of overdose cases were reported during premarketing studies of venlafaxine. In most of these cases, no symptoms were reported {01} {03}. However, there have been postmarketing reports of fatalities occurring with venlafaxine overdose, predominantly when alcohol or other drugs were co-ingested {01}{03}
Overdosage with venlafaxine may result in development of the serotonin syndrome {34}, a potentially fatal hyperserotonergic state. Symptoms include agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes (confusion, hypomania), myoclonus, shivering, and tremor {36}. The non-specific serotonergic receptor antagonists cyproheptadine and methysergide have been reported to be of some use in shortening the duration of the serotonin syndrome {36}.



Treatment of overdose
There is no specific antidote for venlafaxine {01} {02} {03}. Treatment is essentially symptomatic and supportive {01} {02} {03}.


To decrease absorption:
Considering use of activated charcoal {01} {02} {03} or gastric lavage {01} {02} {03}.



Monitoring:
Monitoring cardiac function and vital signs {01} {02} {03}.



Supportive care:
Ensuring adequate airway patency, oxygenation, and ventilation {01} {02} {03}. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Note: Due to the large volume of distribution of venlafaxine {01} {02}, forced diuresis, dialysis, hemoperfusion, or exchange transfusion is not likely to be of benefit {01} {02} {03}. In six patients undergoing hemodialysis, less than 5% of an administered dose of venlafaxine was recovered in dialysis fluid as venlafaxine and O-desmethylvenlafaxine (ODV) {06}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Venlafaxine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to venlafaxine





Breast-feeding—Distributed into breast milk; may cause unwanted effects in nursing infant



Contraindicated medications
MAO inhibitors
Other medications, especially serotonergics and other medications or substances with serotonergic activity
Other medical problems, especially blood pressure problems, cardiac disease, or hepatic or renal function impairment

Proper use of this medication
» Compliance with therapy; not taking more or less medicine than prescribed

» Four weeks or more of therapy may be required before antidepressant effects are achieved

Taking with food to lessen gastrointestinal effects

» For extended-release dosage form: Swallowing capsule whole with fluid; not dividing, crushing, chewing, or placing in liquid

» Proper dosing



For prompt-release dosage form—Taking as soon as possible unless it is within 2 hours of next dose; continuing on regular schedule with next dose; not doubling doses {27}


For extended-release dosage form—Taking as soon as possible if remembered the same day; continuing on regular schedule with next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

» Notifying physician immediately if any signs or symptoms of allergic reaction, such as skin rash or hives, occur {01} {03}

Checking with physician before discontinuing medication

Avoiding use of alcoholic beverages; not taking other CNS depressants unless prescribed by physician

» Caution when driving or doing other jobs requiring alertness, judgment, or clear vision until effects of medication are known

» Possible dizziness or lightheadedness; caution when getting up from a lying or sitting position


Side/adverse effects
Possibility of discontinuation symptoms

Signs of potential side effects, especially headache; hypertension; sexual dysfunction; vision disturbances; cardiovascular effects, other; CNS effects; tinnitus; dyspnea; edema; itching or skin rash; mania or hypomania; menstrual changes; orthostatic hypotension; seizures; urinary effects


General Dosing Information
Abrupt discontinuation of venlafaxine may result in symptoms of withdrawal including anorexia, asthenia, changes in dreaming, diarrhea, dizziness, dryness of mouth, headache, increased sweating, insomnia, nausea, nervousness, and somnolence {01} {02} {03}. It is recommended that patients taking venlafaxine for longer than 1 week be tapered off the drug {01} {02} {03}; venlafaxine should be discontinued gradually over 2 weeks or longer in patients receiving therapy for 6 weeks or longer {02} {03}. In clinical trials, the extended-release dosage form was tapered in decrements of 75 mg per day at 1-week intervals {01}.

Potentially suicidal patients should not have access to large quantities of this medication since depressed patients, particularly those who may use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs. Some clinicians recommend that the patient be supplied with the smallest quantity of medication necessary for satisfactory patient management. {01} {02}

Activation of hypomania or mania has been reported in depressed patients treated with venlafaxine {01} {02} {05}.

Patients receiving the prompt-release dosage form of venlafaxine may change to the extended-release dosage form at the most nearly equivalent mg per day dosage available {03}{40}.

Diet/Nutrition
Venlafaxine should be taken with food to lessen gastrointestinal side effects {01} {02} {04} {10} {17} {20}.


Oral Dosage Forms

Note: The available dosage forms contain venlafaxine hydrochloride, but dosage and strength are expressed in terms of the base.


VENLAFAXINE EXTENDED-RELEASE CAPSULES

Usual adult dose
Antidepressant
Oral, initially 75 mg (base) a day in a single dose, taken with food, in the morning or evening {01}. Some patients may require an initial dosage of 37.5 mg (base) a day for four to seven days in order to adjust to the medication {01}. The dosage may be increased, as needed and tolerated, in increments of 75 mg a day at intervals of at least four days {01}.

Anxiety
Oral, initially 75 mg (base) a day in a single dose, taken with food, in the morning or evening{40}. Some patients may require an initial dosage of 37.5 mg (base) a day for four to seven days in order to adjust to the medication{40}. The dosage may be increased, as needed and tolerated, in increments of 75 mg a day at intervals of at least four days{40}.

[Hot Flashes ]1
Oral, initially 35 mg a day. The dosage may be increased up to 150 mg a day if no reduction in hot flashes occurs after 1 to 2 weeks.{41}{42}{43}{44}{45}{46}{47}{48}{49}


Note: Patients with moderate hepatic function impairment should receive an initial dosage reduction of 50% {01}. Patients with renal function impairment should receive an initial dosage reduction of 25 to 50% {01}. The total daily dose for patients undergoing hemodialysis should be reduced by 50% and the dose should be administered after completion of the dialysis session {01}.


Usual adult prescribing limits
225 mg per day {01}. The maximum recommended dosage of 225 mg per day reflects experience in moderately depressed outpatients {01}. However, severely depressed inpatients in a study using the prompt-release dosage form responded to dosages up to 375 mg per day {01}. There is little experience with the extended-release dosage form at dosages above 225 mg per day, and whether severely depressed patients will respond to higher dosages has not been established {01}.

Usual pediatric dose
Safety and efficacy have not been established {01}.

Usual geriatric dose
See Usual adult dose {01}.

Note: Although no special dosage adjustments based on age are recommended generally {01}, some clinicians recommend a reduced initial dosage and more gradual dosage increases in elderly patients {39}.


Strength(s) usually available
U.S.—


37.5 mg (base) (Rx) [Effexor XR (cellulose) (ethylcellulose) (gelatin) (hydroxypropyl methylcellulose) (iron oxide) (titanium dioxide){01}]


75 mg (base) (Rx) [Effexor XR (cellulose) (ethylcellulose) (gelatin) (hydroxypropyl methylcellulose) (iron oxide) (titanium dioxide){01}]


150 mg (base) (Rx) [Effexor XR (cellulose) (ethylcellulose) (gelatin) (hydroxypropyl methylcellulose) (iron oxide) (titanium dioxide){01}]

Canada—


37.5 mg (base) (Rx) [Effexor XR{37}]


75 mg (base) (Rx) [Effexor XR{37}]


150 mg (base) (Rx) [Effexor XR{37}]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F) {01} in a well-closed container unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Swallow capsules whole. Do not break or chew.
   • Take with food.

Note: Release of venlafaxine from extended-release capsule is membrane-controlled and is not dependent upon pH {01}.



VENLAFAXINE TABLETS

Usual adult dose
Antidepressant
Oral, initially 75 mg a day {02} {03} {10}, administered in two or three divided doses {02} {03} {10} and taken with food {02} {03} {10} {20}. The dosage may be increased, as needed and tolerated, in increments up to 75 mg a day {02} {03} at intervals of no less than four days {02} {03}, up to 225 mg a day {02} {03}. Although dosages over 225 mg a day have not been shown to be useful in moderately depressed outpatients, more severely depressed patients may respond to dosages of up to 375 mg a day, administered in three divided doses {02} {03}.

Note: Some clinicians recommend an initial dosage of 50 mg a day administered in two divided doses in the treatment of mild depression in order to minimize nausea {35}.
In patients with moderate to severe hepatic function impairment—


Dosage reductions of 50% or more are recommended {02} {03}.
In patients with renal function impairment—


Mild to moderate: Dosage reductions of 25% are recommended {02} {03}.


Moderate to severe (CL cr < 30 mL/min): Dosage should be reduced by 50% {06}. The dose may be administered once a day because of the prolonged half-life {06}.


In dialysis patients: Total daily dose should be reduced by 50%, and administration withheld until dialysis treatment is completed {02} {03}.



Usual adult prescribing limits
375 mg a day {02} {03} {28}.

Usual pediatric dose
Safety and efficacy in children up to 18 years of age have not been established {02} {03}.

Usual geriatric dose
See Usual adult dose.

Note: Although no special dosage adjustments based on age are recommended generally {01} {02} {03}, some clinicians recommend a reduced initial dosage and more gradual dosage increases in elderly patients {39}.


Strength(s) usually available
U.S.—


25 mg (base) (Rx) [Effexor (scored) ( cellulose) (iron oxides) ( lactose) (magnesium stearate) ( sodium starch glycolate){03}]


37.5 mg (base) (Rx) [Effexor (scored) ( cellulose) (iron oxides) ( lactose) (magnesium stearate) ( sodium starch glycolate){03}]


50 mg (base) (Rx) [Effexor (scored) ( cellulose) (iron oxides) ( lactose) (magnesium stearate) ( sodium starch glycolate){03}]


75 mg (base) (Rx) [Effexor (scored) ( cellulose) (iron oxides) ( lactose) (magnesium stearate) ( sodium starch glycolate){03}]


100 mg (base) (Rx) [Effexor (scored) ( cellulose) (iron oxides) ( lactose) (magnesium stearate) ( sodium starch glycolate){03}]

Canada—


37.5 mg (base) (Rx) [Effexor (scored) ( cosmetic brown iron oxide) (ferric oxide NF yellow ) (lactose NF hydrous) ( magnesium stearate NF) (microcrystalline cellulose NF) (sodium starch glycolate NF){02}]


75 mg (base) (Rx) [Effexor (scored) ( cosmetic brown iron oxide) (ferric oxide NF yellow ) (lactose NF hydrous) ( magnesium stearate NF) (microcrystalline cellulose NF) (sodium starch glycolate NF){02}]

Packaging and storage:
Store in a dry place between 20 and 25 °C (68 and 77 °F) in a well-closed container {03} unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food.



Revised: 03/07/2003



References
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  1. Effexor package insert (Wyeth-Ayerst—US), Rev 4/18/97, Rec 12/08/97.
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