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Venlafaxine Hydrochloride

Pronunciation: (VEN-la-FAX-een HYE-droe-KLOR-ide)
Class: Serotonin and norepinephrine reuptake inhibitor (SNRI)

Trade Names:
Effexor
- Tablets 25 mg
- Tablets 37.5 mg
- Tablets 50 mg
- Tablets 75 mg
- Tablets 100 mg

Trade Names:
Effexor XR
- Capsules, ER 37.5 mg
- Capsules, ER 75 mg
- Capsules, ER 150 mg

Trade Names:
Venlafaxine
- Tablets, ER 37.5 mg
- Tablets, ER 50 mg
- Tablets, ER 75 mg
- Tablets, ER 100 mg
- Tablets, ER 225 mg

Novo-Venlafaxine XR (Canada)

Pharmacology

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Potentiates norepinephrine, serotonin, and dopamine neurotransmitter activity in the CNS by inhibiting their neuronal reuptake.

Pharmacokinetics

Absorption

Absolute bioavailability is 45% and a single oral dose is well absorbed (at least 92%). Steady-state concentrations of venlafaxine and O-desmethylvenlafaxine (ODV) in plasma are attained within 3 days of oral dosing. Exhibits linear kinetics over dose range of 75 to 450 mg/day. For ER, C _max is 150 ng/mL (260 ng/mL for ODV) and T _max is 5.5 h (9 h for ODV).

Distribution

Vd is 7.5 L/kg (5.7 L/kg for ODV); 27% of venlafaxine and 30% of ODV is protein bound.

Metabolism

Extensively metabolized in the liver. The only major metabolite is ODV, which is active.

Elimination

Renal elimination of venlafaxine and its metabolite is the primary route of excretion. Within 48 h, 87% is recovered in urine. Elimination half-life is 5 h (11 h for ODV).

Special Populations

Renal Function Impairment

Dosage adjustment is necessary with CrCl 10 to 70 mL/min. Venlafaxine half-life was prolonged about 50%, and Cl was reduced about 24%; ODV half-life was prolonged 40% although Cl was unchanged.

Dialysis

Dose adjustment is necessary. Venlafaxine half-life was prolonged about 180%, and Cl was reduced about 57%. ODV half-life was prolonged about 142%, and Cl was reduced 56%.

Hepatic Function Impairment

In patients with hepatic cirrhosis, dosage adjustment is necessary. Venlafaxine half-life was prolonged to about 30%, Cl decreased 50%; ODV half-life was prolonged about 60%, and Cl decreased 30%.

Elderly

Pharmacokinetics not altered by age.

Gender

Pharmacokinetics not altered by gender.

Indications and Usage

ER capsules, ER tablets, immediate-release tablets

Treatment of major depressive disorder (MDD).

ER capsules, ER tablets

Treatment of social anxiety disorder.

ER capsules

Generalized anxiety disorder, panic disorder.

Unlabeled Uses

Autism; binge eating disorder; hot flashes; pain; premenstrual dysphoric disorder; posttraumatic stress disorder.

Contraindications

Concomitant use with MAOIs; hypersensitivity to venlafaxine or any component in the formulation.

Dosage and Administration

MDD
Adults (immediate-release)

PO 75 mg/day in 2 or 3 divided doses; titrate to clinical effect, adding up to 75 mg/day at intervals of at least 4 days (max, 375 mg/day).

Adults (ER capsules, ER tablets)

PO 75 mg/day administered as single dose either in the morning or evening at approximately same time once daily. Some patients may need to start at 37.5 mg/day for 4 to 7 days before increasing to 75 mg/day. Titrate to clinical effect in increments of up to 75 mg/day at intervals of no less than 4 days (max, 375 mg/day).

Generalized Anxiety Disorder
Adults (ER capsules)

Social Anxiety Disorder
Adults (ER tablets, ER capsules)

PO 75 mg daily. There is no evidence that higher doses confer any additional benefit.

Panic Disorder
Adults (ER capsules)

PO Start with 37.5 mg/day for 7 days as a single dose either in the morning or evening at approximately the same time once daily. After 7 days, the dosage may be increased to 75 mg/day for 7 days. Subsequent dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of no less than 7 days (max, 225 mg/day).

Switching From Venlafaxine to Venlafaxine ER

Depressed patients on venlafaxine can be switched to venlafaxine ER at the nearest equivalent total daily dose.

Switching Patients To and From MAOIs

When switching from an MAOI to venlafaxine, allow at lease 14 days after discontinuing the MAOI before starting venlafaxine. Allow at least 7 days after discontinuing venlafaxine before starting an MAOI.

Hepatic Function Impairment
Adults

PO Reduce total daily dose by 50% in patients with mild to moderate hepatic function impairment.

Renal Function Impairment
Adults

PO Reduce ER total daily dose by 25% to 50% in patients with renal function impairment (CrCl 10 to 70 mL/min). Reduce total daily dose of immediate-release by 25% in patients with mild to moderate renal function impairment. Reduce total daily dose of ER and immediate-release by 50% in patients undergoing hemodialysis. Withhold dose until dialysis treatment is completed.

General Advice

Administer with food.
It is generally agreed that acute episodes of MDD require several months or longer with sustained pharmacological therapy beyond response to the acute episode.
Swallow venlafaxine ER capsules or tablets whole. Do not divide, crush, chew, or place in water.
For patients who have difficulty swallowing venlafaxine ER capsules whole, the capsules may be opened and the contents sprinkled on a spoonful of applesauce. The drug/applesauce mixture should be swallowed immediately without chewing and followed with a glass of water. Do not prepare the mixture ahead of time and store.

Storage/Stability

ER capsules and immediate-release tablets

Store at controlled room temperature (68° to 77°F). Protect from moisture.

ER tablets

Store at 59° to 86°F. Protect from moisture and humidity.

Drug Interactions

Aspirin, NSAIDs

The risk of GI bleeding may be increased.

Azole antifungal agents (eg, ketoconazole)

Venlafaxine plasma levels may be elevated, increasing the risk of adverse reactions.

Cimetidine

Venlafaxine plasma concentrations may be increased. Caution is advised in patients with hypertension or hepatic function impairment.

Clozapine

Plasma levels of clozapine may be increased.

CNS-active drugs (eg, serotonin reuptake inhibitors [eg, fluoxetine], lithium)

Because this interaction has not been studied, caution is warranted when coadministering these agents with venlafaxine.

CYP3A4 inhibitors

Venlafaxine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions; use with caution.

Cyproheptadine

Decreased pharmacologic effects of venlafaxine may occur.

Desipramine, haloperidol

Plasma levels of these drugs may be elevated by venlafaxine, increasing the risk of adverse reactions.

Indinavir

Plasma concentrations may be decreased by venlafaxine.

Linezolid, lithium, methylene blue, metoclopramide, selective 5-HT ₁ receptor agonists (eg, sumatriptan), sibutramine, SNRIs, SSRIs, tramadol, trazodone

Serotonin syndrome, including irritability, increased muscle tone, shivering, myoclonus, and altered consciousness, may occur.

MAOIs

MAOIs have produced serious, even fatal, reactions when given concomitantly with venlafaxine. Do not use venlafaxine together with MAOIs or within 14 days of MAOI use. Wait at least 7 days after stopping venlafaxine before using MAOIs.

Metoprolol

Coadministration increased metoprolol concentrations by approximately 30% to 40%.

Risperidone

Coadministration results in an approximately 32% increase in risperidone AUC.

St. John's wort

Increased sedative-hypnotic effects may occur.

Sympathomimetics (eg, amphetamine)

Increased sensitivity to sympathomimetics and increased risk of serotonin syndrome.

Warfarin

May increase PT, aPT, or INR with coadministration.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Vasodilation (6%); hypertension (5%); palpitation (3%); tachycardia (2%); postural hypotension (1%); deep vein thrombophlebitis, ECG abnormalities (eg, QT prolongation), cardiac arrhythmias (including atrial fibrillation, torsades de pointes) (postmarketing).

CNS

Headache (38%); somnolence (26%); dizziness, insomnia (24%); nervousness (21%); asthenia (19%); anxiety (11%); tremor (10%); abnormal dreams (7%); agitation (5%); depression, hypertonia, paresthesia, twitching (3%); abnormal thinking, confusion (2%); amnesia, hypesthesia, migraine, trismus, vertigo (at least 1%); depersonalization (1%); catatonia, delirium, extrapyramidal symptoms, impaired coordination and balance, involuntary movements, NMS-like events, panic, serotonin syndrome, shock-like electrical sensations (postmarketing).

Dermatologic

Sweating (19%); rash (3%); pruritus (1%); erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

EENT

Abnormality of accommodation (9%); pharyngitis (7%); abnormal vision (6%); mydriasis, sinusitis, taste perversion, tinnitus (2%); angle-closure glaucoma, eye hemorrhage (postmarketing).

GI

Nausea (58%); dry mouth (22%); anorexia (20%); constipation (15%); abdominal pain, diarrhea, vomiting (8%); dyspepsia (7%); flatulence (4%); eructation (2%); increased appetite (at least 1%); GI bleeding (postmarketing).

Genitourinary

Abnormal ejaculation (19%); impotence (10%); decreased libido (9%); impaired urination, orgasm disturbance (8%); anorgasmia (female), urinary frequency (3%); albuminuria, metrorrhagia, prostatitis, urination impaired, vaginitis (at least 1%); urinary retention (1%).

Hematologic

Ecchymosis (at least 1%); agranulocytosis, aplastic anemia, neutropenia, pancytopenia (postmarketing).

Hepatic

Hepatic events (including elevated gamma glutamyltransferase; unspecified LFT abnormalities; liver damage, necrosis, or failure; and fatty liver) (postmarketing).

Lab Tests

Increased serum cholesterol (5%); increased CPK and LDH (postmarketing).

Metabolic-Nutritional

Weight loss (4%); edema, weight gain (at least 1%).

Respiratory

Bronchitis, cough increased, dyspnea (at least 1%); interstitial lung disease (postmarketing).

Miscellaneous

Yawn (8%); chills (7%); flu-like syndrome, infection (6%); accidental injury (5%); chest pain, trauma (2%); arthralgia, fever, neck pain, substernal chest pain (at least 1%); anaphylaxis, congenital anomalies, hemorrhage, increased prolactin, night sweats, pancreatitis, pulmonary eosinophilia, renal failure, rhabdomyolysis, SIADH (postmarketing).

Precautions

Warnings

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders. Appropriately monitor patients of all ages who are started on antidepressant therapy and observe them closely for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with their prescriber.

Monitor

Monitor patients for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy or at times of dose changes, either increases or decreases, and during discontinuation of therapy. Monitor serum cholesterol levels in patients receiving long-term therapy. Monitor BP and heart rate at regular intervals.

Periodically reassess patient to determine need for maintenance treatment and the appropriate dose for such treatment.

Pregnancy

Category C . Neonates exposed to venlafaxine late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established. Not approved for use in children. Growth rate reduction and weight loss may occur.

Elderly

Take extra care when increasing dose in elderly patients.

Renal Function

Reduction of dose may be necessary. Use drug with caution.

Hepatic Function

Reduction of dose may be necessary. Use drug with caution.

Hazardous Tasks

May impair judgment, thinking, or motor skills.

Abnormal bleeding

Risk of bleeding events, ranging from ecchymosis to life-threatening hemorrhages, may be increased.

Activation of mania/hypomania

Has been reported. Use cautiously in patients with history of mania.

Appetite changes

Treatment-emergent anorexia in adults and decreased appetite in children are more common in venlafaxine-treated patients compared with placebo.

Blood pressure

Dose-related increases in supine systolic and diastolic BP may occur.

Concomitant illness

Use with caution in patients with diseases or conditions that could affect hemodynamic responses or metabolism and whose underlying medical conditions might be compromised by increases in heart rate (eg, heart failure, hyperthyroidism, recent MI).

Discontinuation of treatment

If treatment is to be discontinued or the dose reduced after more than 1 wk of therapy, gradually taper the dose and monitor patient for withdrawal symptoms. If significant withdrawal symptoms develop, reinstitute previous dosing schedule and attempt a less-rapid tapering regimen after patient has stabilized.

Glaucoma

Mydriasis has been reported. Monitor patients with raised IOP or at risk of acute narrow-angle glaucoma.

Height changes

Growth rate is decreased in pediatric patients receiving venlafaxine compared with placebo. The differences in observed and expected growth rates were greater in children younger than 12 yr of age compared with children 12 yr of age and older.

Hyponatremia

Hyponatremia and/or SIADH may occur. Use with caution in elderly, volume-depleted, or diuretic-taking patients.

Interstitial lung disease and eosinophilic pneumonia

Because these conditions have been associated with venlafaxine, consider the possibility of these adverse reactions occurring in patients presenting with progressive dyspnea, cough, or chest discomfort.

Insomnia and nervousness

Treatment-emergent insomnia and nervousness may occur.

NMS

Life-threatening NMS may occur.

Screening for bipolar disorder

Screen patients with depression for risk of bipolar disorder prior to initiating therapy with an antidepressant.

Seizures

Use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Discontinue use if seizures occur.

Serotonin syndrome

Potentially life-threatening serotonin syndrome, including mental status changes, may occur.

Serum cholesterol

Serum cholesterol levels increased in patients treated for at least 3 months.

Sustained hypertension

May cause sustained increases in BP.

Weight changes

A loss of 5% or more of body weight has been reported in about 7% of patients.

Overdosage

Symptoms

Bradycardia, bundle branch block, coma, convulsions, death, hypotension, liver necrosis, mydriasis, paresthesia, prolonged QTc interval, rhabdomyolysis, seizures, serotonin syndrome, sinus tachycardia, somnolence, ventricular tachycardia, vertigo, vomiting.

Patient Information

Advise patient or caregiver to read patient information leaflet before starting therapy and with each refill.
If patient is a child or adolescent being treated for depression, advise patient, family, or caregiver to read the Medication Guide About Using Antidepressants in Children and Teenagers before starting therapy and with each refill. Review face-to-face monitoring schedule required for use of drug in this situation.
Advise patient that dose will be started low and then increased until max benefit is obtained.
Instruct patient to take prescribed dose with food.
Advise patient using venlafaxine ER capsules or tablets to swallow capsules whole. Caution patient not to separate, crush, or chew the capsules or tablets.
Advise patient who has difficulty swallowing venlafaxine ER capsules whole that the capsules may be opened and the contents sprinkled on a spoonful of applesauce. The drug/applesauce mixture should be swallowed immediately without chewing and followed with a glass of water. Caution patient not to prepare the mixture ahead of time and store.
Instruct patient not to stop taking the medication when they feel better.
Caution patient that unless advised by health care provider, not to take aspirin or aspirin-containing products, NSAIDs, Ginkgo biloba , or any other medication or herb that can affect coagulation because of increased risk of serious bleeding.
Instruct patient to contact health care provider if symptoms do not appear to be getting better, are getting worse, or if bothersome adverse reactions (eg, changes in sexual function, diarrhea, excessive drowsiness, nausea, nervousness, tremors) occur.
Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
Advise patient, family, or caregiver to notify health care provider if rash, hives, or other symptoms of an allergic reaction develop.
Advise patient, family, or caregiver of patient being treated for depression to be alert for abnormal changes in mood or thinking and to immediately report any of the following to health care provider: agitation, akathisia (psychomotor restlessness), anxiety, change in mood, change in personality, hostility or aggressiveness, impulsivity, insomnia, irritability, panic attacks, suicidal thoughts or behavior. Advise families and caregivers of patients to observe for emergence on a day-to-day basis, because changes may be abrupt.
Advise patient that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
Instruct patient to avoid alcoholic beverages and sedatives or depressants (eg, diazepam) while taking medication.
Advise patient with high BP to monitor BP at regular intervals.
Advise patient that drug may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.