Saturday, April 05, 2008

Description and details on Venlafaxine (Effexor) antidepressant drugs

Venlafaxine (Effexor) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class first introduced by Wyeth in 1993. It is prescribed for the treatment of clinical depression and anxiety disorders, among other uses. Due to the pronounced side effects and suspicions that venlafaxine may significantly increase the risk of suicide, it is not recommended as a first line treatment of depression. However, it is often effective for depression not responding to SSRIs. Venlafaxine was the sixth most widely-used antidepressant based on the number of retail prescriptions in the US (17.1 million) in 2006.

Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder in adults.

Effexor is distributed in pentagon-shaped peach-colored tablets of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg. There is also an extended-release version distributed in capsules of 37.5 mg (gray/peach), 75 mg (peach), and 150 mg (brownish red).

Venlafaxine is a bicyclic antidepressant, and is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor. It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). Additionally, in high doses it weakly inhibits the reuptake of dopamine, with recent evidence showing that the norepinephrine transporter also transports some dopamine as well, implying that SNRIs may also increase dopamine transmission. This is because SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex).

Venlafaxine is well absorbed with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine, which is just as potent a serotonin-norepinephrine reuptake inhibitor as the parent compound, meaning that the differences in metabolism between extensive and poor metabolizers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in CYP2D6 poor metabolizers. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys. The half-life of venlafaxine is relatively short, therefore patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in the withdrawal symptoms.

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release version (sometimes referred to as controlled release) controls the release of the drug into the gastrointestinal tract over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of patients suffering from nausea as a side effect resulting in a lower number of patients stopping their treatment due to nausea.

Generic venlafaxine is available in the United States as of August 2006 and in Canada as of December 2006. A generic form of the extended-release version is available in Canada as of January 2007 and will become available in the United States in 2010. Generic versions of both drug forms are available now in India.

Venlafaxine was shown to be effective for depression in multiple double blind studies. Venlafaxine is similar in efficacy to trazodone and tricyclic antidepressants amitriptiline (Elavil) and imipramine and it was better tolerated than amitriptiline. Venlafaxine appears to have efficacy similar or somewhat better than sertraline (Zoloft) and fluoxetine (Prozac) depending on the criteria and rating scales used. In particular, higher doses of venlafaxine are more effective, and more patients achieved remission or were "very much improved". At the same time the efficacy was similar if the number of patients who achieved "response" or were "improved" was considered. A meta-analysis comparing venlafaxine and combined groups of SSRI or tricyclic antidepressants indicated superiority of venlafaxine.
Based on the same set of criteria, venlafaxine was similar in efficacy to an atypical antidepressant bupropion (Wellbutrin); however, the remission rate was significantly lower for venlafaxine.
Venlafaxine was also marginally inferior in efficacy to a newer SSRI escitalopram (Lexapro) and had twice higher frequency of the side effects, in particular, nausea, ejaculation disorder, somnolence and sweating.

A popular magazine Consumer Reports, which in 2004 had rated venlafaxine as the most effective among six commonly prescribed antidepressants, no longer recommends it. Fluoxetine, citalopram and bupropion have been chosen as Consumer Reports Best Buy drugs in the updated version of their guide, based upon effectiveness, safety, side effects, and cost.

Venlafaxine is not recommended in patients hypersensitive to venlafaxine. It should not be taken by anyone who is allergic to the inactive ingredients, which include gelatin, cellulose, ethylcellulose, iron oxide, titanium dioxide and hypromellose. It should never be used in conjunction with a monoamine oxidase inhibitor (MAOI), due to the potential to develop a potentially deadly condition known as serotonin syndrome. At least 14 days time lag are required between the intake of venlafaxine and MAO inhibitors.

Caution should also be used in those with a seizure disorder. Venlafaxine is not approved for use in children or adolescents. However, Wyeth does provide information on precautions if venlafaxine is prescribed to this age group for the treatment of non-approved conditions. Studies in these age groups have not established its efficacy or safety.

The prescribed dosage of venlafaxine may have to be adjusted for those with liver, thyroid or kidney problems. It is crucial to inform a doctor of any such disorders before taking venlafaxine.

Venlafaxine can increase eye pressure, so those with glaucoma should inform their doctors before taking venlafaxine. More frequent eye checks may be necessary.

The FDA has asked the sponsors of all SNRIs to include the potential risk for persistent pulmonary hypertension (PPHN) in prescribing data as of July 19, 2006. Medications containing Venlafaxine caused a mean heart rate increase of 4 b.p.m in clinical trials, along with a sustained increase in blood pressure in some.

The development of a potentially life-threatening serotonin syndrome may occur with Effexor XR treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs, and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

As with most antidepressants, lack of sexual desire is a common side effect. In trials, delayed ejaculation and delayed orgasm occurred in 8-16% of men. Delayed orgasm occurred in 2-8% of women. Venlafaxine can raise blood pressure at high doses, so it is contraindicated for persons with hypertension.

It has a higher rate of treatment emergent mania than many modern antidepressants, and many people find it to be a more activating medication (one that increases energy or wakefulness) than other antidepressants.[citation needed] Paradoxically, some users find it highly sedating and find that it must be taken in the evening.

There have been false positive phencyclidine (PCP) results caused by Venlafaxine with certain on-site routine urine-based drug tests. Positive on-site results should always be sent to a qualified drug testing laboratory for confirmation before any action is taken against the employee.

The percentage of occurrences for each side effect listed comes from clinical trial data provided by Wyeth Pharmaceuticals Inc. The percentages indicate the percentage of people that experienced the side effect in clinical trials.

* Nausea (21-35%)
* Headache (34%)
* Apathy
* Constipation
* Ongoing Irritable Bowel Syndrome
* Dizziness (11-20%)
* Fatigue
* Insomnia (15-23%)
* Vertigo
* Dry mouth (12-16%)
* Sexual dysfunction (14-34%)
* Sweating (10-14%)
* Orthostatic hypotension (postural drop in blood pressure)
* Vivid dreams (3-7%)
* Impulsive Actions
* Increased blood pressure
* Decreased Appetite (8-20%)
* Electric shock-like sensations also called "Brain zaps"
* Increased anxiety at the start of treatment
* Akathisia (Agitation) (3-4%)
* Memory Loss

A comparison of adverse event rates in a fixed-dose study comparing venlafaxine 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine use. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value <= 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities. Venlafaxine's toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants than the SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity. Deaths have been reported following very large doses.

There is no specific antidote for venlafaxine and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anti-convulsants. Forced diuresis, hemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug's high volume of distribution.

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