Drug Whys
by Mike McEvoy
04/21/2011

Venlafaxine (Effexor)� Drug Whys


Generic Name: Venlafaxine (multiple generics available)
Common Brand Name: Effexor® and Effexor XR (Wyeth Pharmaceuticals – U.S.)
Popularity: 31st most commonly prescribed drug between 2002-2009 (U.S.)
Class: SSRI (selective serotonin reuptake inhibitor), antidepressant

Treatment Uses 
For treatment of generalized anxiety disorder, major depressive disorder, panic disorder (with or without agoraphobia), or social phobia. Venlafaxine has been used with favorable results in treatment of attention deficit hyperactivity disorder (ADHD) in children, and in binge eating disorders, acute bipolar depression, and dysthymic disorder in adult patients.

It has also helped with treatment of cancer pain and shown effectiveness in post-stroke as well as perimenopausal depression, menopausal flushing, premenstrual dysphoric disorder and breast cancer related hot sweats.

Venlafaxine is useful in prevention of tension-type headache. Some data suggest that venlafaxine may be useful in treating obsessive-compulsive disorder (OCD) and post traumatic stress disorder (PTSD); studies are ongoing. Studies of venlafaxine for treating symptoms of diabetic neuropathy and neurotoxicity associated with cancer chemotherapy have thus far been inconclusive.

The FDA has also added a Black Box warning (their highest level advisory) to venlafaxine stating, "Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders."

Prescribers are cautioned to consider this risk. Venlafaxine is not approved for use in children; however, that does not stop prescribers from writing for it when they feel compelled to do so. In the United States, outpatient dispensing of any new or refill antidepressant prescriptions to children, adolescents and young adults must be accompanied by an FDA approved medication guide (see: www.fda.gov/cder/Offices/ODS/medication_guides.htm).

Venlafaxine is an SSRI which, as a class of antidepressants, has all but replaced a much older class called tricyclic antidepressants (TCAs). One major advantage, as any older medic can recall, is that SSRIs have a far less lethal overdose profile than TCAs.

Dosing and Administration
The recommended initial dose of venlafaxine for generalized anxiety disorder or major depressive disorder in adults is 37.5 to 75 milligrams extended release (XR) formulation, taken orally once daily. For major depressive disorder, immediate release tablets should be started at 75 milligrams orally, divided into two or three daily doses.

Both extended release and immediate release doses can be increased by 75 milligrams per day at four day intervals up to a maximum daily dose of 225 milligrams per day for outpatients or 375 milligrams daily for inpatients.

Continued assessment is warranted as maintenance doses may be less than the dose needed to achieve an initial response. For panic disorder, initial extended release dosing should start at 37.5 milligrams daily for seven days, with weekly increases of 75 milligrams per day thereafter to a maximum daily dose of 225 milligrams. For social phobia, 75 milligrams extended release formulation once daily is the recommended starting and maintenance dose.

Once stabilized on immediate release venlafaxine, depressed patients can be converted to the equivalent extended release dosing on a milligrams per day basis.

Venlafaxine dosing for children and adolescents with ADHD is recommended to start at 12.5 milligrams daily. For children weighing less than 40 kilograms, dose increases of 12.5 milligrams daily at weekly intervals to a maximum of 50 milligrams per day are recommended, given in two divided doses. Children more than 40 kilograms can be increased by 25 milligrams daily each week to a maximum of 75 milligrams daily in 3 divided doses. The mean pedi dose (for reference purposes) is 60 milligrams, or 1.4 milligrams per kilogram each day, divided into two or three doses. Note that venlafaxine is not FDA approved for use in children. Dosing recommendations come from published research.

Food has no effect on absorption or availability of venlafaxine in the body and morning or evening dosing appears to offer no distinct advantages. It is recommended that dose(s) be taken with food at the same time each day. Extended release capsules and tablets should be swallowed whole with fluid.

Immediate release capsules can be opened and their contents sprinkled on a spoonful of applesauce for immediate swallowing, followed by a glass of water. Extended release capsules and tablets should not be divided, crushed, chewed, or mixed with water.

In patients with mild to moderate renal impairment, the total daily dose of venlafaxine should be reduced by 25 to 50 percent. Total daily dose should be reduced by 50 percent in dialysis patients. In mild to moderate hepatic insufficiency, the total daily dose should be reduced by 50 percent.

It may be necessary to reduce doses further in patients with cirrhosis. While clearance of venlafaxine is reduced by about 15 percent in the elderly, dose adjustments are not necessary although caution should be exercised in titrating dosages upward in older patients.

Overdoses of up to 6.75 grams of venlafaxine have been reported. Most patients were asymptomatic. Patients with symptoms recovered without long term effects. Recent reports have typically involved overdoses of venlafaxine, alcohol and other drugs. These suggest that overdoses of venlafaxine should raise suspicion of multi-drug involvement.

In these cases, symptoms most often included tachycardia, altered level of consciousness, mydriasis (persistently dilated pupils), seizures, and vomiting. Overdoses of venlafaxine may be associated with greater risk of death than other SSRIs, but clearly less than TCAs (tricyclic antidepressants). Of note, venlafaxine can cause a false-positive result in urine tests for PCP. Dialysis does not remove venlafaxine.

Pharmacology/Pharmacokinetics/Stability 
Following oral administration, time to peak concentration in the bloodstream for immediate release preparations is 1 to 2 hours and 5.5 hours for extended release doses. When equal daily doses are administered, the available venlafaxine with immediate release versus extended release preparations is similar.

Steady state levels of venlafaxine are achieved after three days of regular dosing. Some improvement in symptoms of major depression may occur within two weeks. Overall improvement usually takes several months or longer.

Venlafaxine is extensively metabolized in the liver. The kidneys excrete 87 percent of venlafaxine in the urine and 2 percent of each dose is excreted in the feces. Elimination is significantly diminished in patients with liver or kidney dysfunction.

Venlafaxine is generally well tolerated in pregnancy and does not appear to pose an unusually high risk to the developing fetus until the third trimester. Neonates exposed to venlafaxine and other SSRIs late in the third trimester of pregnancy have experienced complications requiring prolonged hospitalization, mechanical ventilation and tube feeding.

Clinicians are advised to taper SSRIs during the third trimester. Venlafaxine is excreted in human breast milk. Limited studies suggest no evidence of adverse effects. The dangers of failing to treat major depression are significant and must be weighed against potential for harm to the baby.

Venlafaxine's mechanism of action in the body is believed to be associated with potentiation of neurotransmitter activity in the central nervous system.

Venlafaxine comes in multiple strengths, depending on manufacturer. Size, shape and color also vary; typical strengths of 37.5, 75 and 150 milligram capsules and tablets are available, all in either immediate release or extended release form. Immediate release tablets are also available in 25, 50 and 100 milligram strengths and extended release tablets also come in a 225 milligram strength. Venlafaxine tablets should be stored at room temperature (between 68 and 77 F).

Cautions and Warnings
Aside warnings on worsening of depression and risk of suicide, the most significant warnings pertain to use with monoamine oxidase inhibitors (MAOIs). Once a widely prescribed antidepressant, MAOIs are now uncommon, and reserved for patients who don't respond to newer (and safer) agents. Use of venlafaxine in patients taking or who have taken an MAOI within the past 14 days can lead to a fatal serotonin syndrome.

This syndrome resembles malignant hyperthermia with rigidity, extremely high fevers, and a constellation of other physical effects resulting from excessive levels of serotonin in the brain. A minimum of two weeks separation between use of venlafaxine and MAOIs is imperative.

Venlafaxine should be discontinued at least seven days prior to starting an MAOI. Abruptly stopping venlafaxine can result in another constellation of distressing symptoms including abnormal movements and sensations. Dosing should be tapered gradually when discontinuing therapy.

If a patient has been taking venlafaxine for six weeks or longer, it should be tapered over at least two weeks. Caution is recommended when using venlafaxine in patients with known seizure disorders. Patients should be aware that venlafaxine may cause an increase in anxiety, nervousness, or insomnia. In some patients, these side effects may outweigh benefits.

There is also an increased risk of bleeding with venlafaxine, especially when used in combination with NSAIDs, aspirin, warfarin or other anticoagulants. The precise risk is difficult to quantify but reportedly ranges from increased bruising and nosebleeds to major hemorrhage.

Clinically significant elevations in cholesterol have been reported in 5.3 percent of patients treated with venlafaxine for more than three months.

Suicide risk is a concern in any depressed patient, and with SSRIs, particularly younger patients; initiating treatment does not instantly diminish suicide risk. Despite newer and safer antidepressants, some 30 to 40 percent of depressed patients fail to obtain remission and suffer continued symptoms or relapse.

Caution is warranted with any high-risk patient until remission of depression occurs. Families and significant others should be advised to closely observe patients for clinical worsening, suicidality, or unusual changes in behavior.

Prescriptions should be written for the smallest quantity of medication needed for good patient care with the thought in mind of minimizing danger from an overdose. With long-term therapy, periodic monitoring of heart rate, blood pressure, serum sodium, liver function, renal function, cholesterol and blood counts is advised.

There is a single case report in the literature of a patient who developed acute narrow angle glaucoma with venlafaxine, which somehow prompted the manufacturer to recommend monitoring intraocular pressures during treatment. The actual incidence does not suggest this as a serious concern.

Important Side Effects and Interactions
Headache is reported by 25 to 38 percent of patients, as is nausea (21 to 58 percent), somnolence (12 to 26 percent), xerostomia (dry mouth, by 12 to 22 percent), dizziness (11 to 24 percent), insomnia (15 to 24 percent), anorexia (loss of appetite, by 8 to 17 percent), constipation (8 to 15 percent), diarrhea (8 percent), excessive sweating (7 to 19 percent), nervousness (6 to 21 percent), visual disturbances (6 to 9 percent), and anxiety (2 to 11 percent). Unlike other SSRIs, weight loss exceeding 5 percent occurs in some 7 percent of patients, likely related to anorexia. This does not imply that venlafaxine should be prescribed as a weight loss drug. Between 2 and 19 percent of (male) patients report delayed ejaculation. SSRIs are often prescribed as a treatment for premature ejaculation.

Sustained increases in blood pressure have been reported in patients taking therapeutic doses of venlafaxine with a dose dependent incidence ranging between 3 and 13 percent. A mean increase in heart rate of 3 beats per minute has also been noted in studies. There were no appreciable changes in QTc intervals (hence no propensity for pro-arrhythmic effects).

Currently, there are 158 drugs reported to interact with venlafaxine. Of these, none are significant to prehospital and emergency medicine providers.

Average Costs – U.S.
• 37.5 mg/75 mg/150 mg tablet (generic)*
Patient cost: $0.85 each immediate release, $4.83 each XR (extended release)
Large Hospital cost: $0.32 each immediate release, $3.39 each XR
*Wal Mart® and Target don't include this med in their $4/month programs

References:
1. MICROMEDEX Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed February, 2011).
2. Albany Medical Center Pharmacy, Albany, New York.




Mike McEvoy, PhD, REMT-P, RN, CCRN is the EMS Coordinator for Saratoga County, New York, a paramedic for Clifton Park-Halfmoon Ambulance, and Chief Medical Officer for West Crescent Fire Department. He is a clinical specialist in cardiac surgery and teaches critical care medicine at Albany Medical College. Mike is the EMS editor for Fire Engineering magazine, a popular speaker at EMS, fire, and medical conferences, and lead editor of the Jones & Bartlett textbook, "Critical Care Transport". In his free time, he is an avid hiker and winter mountain climber. Contact Mike at mike.mcevoy@ems1.com.

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