1

Use

Adderall was introduced in 1996 as instant-release tablets, which has since become available as the generic formulation "mixed amphetamine salts." The active ingredients of Adderall include a combination of dextroamphetamine and racemic amphetamine salts. Shire later introduced a gradual-release preparation of these ingredients, Adderall XR (extended release), and retains patent rights on Adderall XR that will expire in 2007.

In particular, Adderall XR is comprised of the following proportions of active ingredients:

1/4 Dextroamphetamine Saccharate
1/4 Dextroamphetamine Sulfate
1/4 dl-amphetamine Aspartate (racemic amphetamine)
1/4 dl-amphetamine Sulfate (racemic amphetamine)

The four component salts are claimed to be metabolized at different rates, thereby imparting a more gradual and "smoother" build-up and decline in effect compared to amphetamine preparations comprising only a single salt.

The average elimination half-life for dextroamphetamine is 10 hours in adults, and for levoamphetamine, 13 hours. Its effects are otherwise similar to other central nervous system stimulants (see amphetamine for details.).

The manufacturer claims that the mixture of salts makes Adderall's effects smoother, with softer highs and lows, than those of other treatments for the same disorders.

There is little evidence, however, to support this claim for immediate-release. A recent patent application for Adderall (USP #6,384,020) was a pharmaceutical composition patent listing a rapid immediate release oral dosage form. No claim of increased or smooth drug delivery was made. A recent double-blind, placebo-controlled crossover study, conducted among children, indicated that patients behaved similarly to other immediate release amphetamines. The authors found that sustained-release dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, and cost less than Adderall, though dexamphetamine was less effective in the first few hours.[1]

Adderall is now sold in either an immediate-release tablet or an extended-release capsule, marketed as Adderall XR (for "eXtended Release"). Doses for both immediate-release and extended-release form come in 5, 10, 15, 20, 25 and 30 mg increments.

Adderall XR utilizes the Microtrol® delivery system to achieve the extended-release mechanism. This delivery system incorporates two beads: the first type of bead dissolves immediately and the second type releases four hours later. Maximum plasma concentration is achieved in seven hours, compared to regular Adderall IR (immediate-release) which reaches maximum plasma concentration within three hours. As a result of its high bioavailability, Adderall XR's effectiveness is not altered by food absorption in the gastrointestinal tract. However, tmax (mean plasma concentration) is prolonged by 2.5 hours (using a standard high-fat meal as the control). Acidic beverages should not be ingested with Adderall XR as they alter the pH balance of the stomach.[2]

Effects

While the exact mechanism is unknown, it is believed that Adderall works by blocking the reuptake of dopamine and norepinephrine into the presynaptic neuron and increasing their release from the presynaptic neuron into the extraneuronal space. In other words, Adderall reverses the reuptake mechanism, turning it into a pump instead of a vacuum. Sources note that amphetamine and related compounds (ephedrine, etc.) displace noradrenaline from the presynaptic neuron and do not act as reuptake inhibitors as referenced above. ^{[citation
needed]}

The increased flow of dopamine and norepinephrine into the extraneuronal space causes the patients' brain, as one psychiatrist explains,^{[citation
needed]} to experience a more intense level of concentration, causing an increased ability to focus for extended periods of time, and a heightened interest in performing focus based tasks.

Some patients feel they are less creative while taking Adderall, while others report that it can aid in creative work.^{[citation
needed]} The famous Beat generation writer Jack Kerouac, for instance, is said to have written much of his classic On The Road in a span of three weeks, aided by amphetamine (an active ingredient in Adderall) from Benzedrine inhalers; country music star Johnny Cash had a long period of amphetamine use in the 1960s; and mathematician Paul Erdős was noted for habitual use of prescription amphetamine throughout the final decades of his life; Smile was written by Brian Wilson and Van Dyke Parks with heavy amphetamine use, among others. All of these probably knew the drug by its common name, speed.

Double-blind, placebo-controlled studies of dextroamphetamine in normal subjects have shown significant performance increases on cognitive tasks and decreased reaction time. http://www.sciencemag.org/cgi/content/abstract/199/4328/560

Amphetamines have been shown to pass through into breast milk. Because of this, mothers taking medications containing amphetamines are advised to avoid nursing during their course of treatment. (http://www.fda.gov/cder/foi/label/2004/021303s005lbl.pdf)

Side effects

Common side effects of Adderall used as prescribed include: dry mouth, loss of appetite, difficulty falling asleep, headache, weight loss and erectile dysfunction

Less common side effects

Some information in this article or section has not been verified and may not be reliable.
Please check for inaccuracies, and modify and cite sources as needed.

Less common side effects of Adderall used as prescribed include:Upset stomach, Nervousness, Mydriasis, Bruxism (teeth grinding), Urinary retention, Pyrexia, Tachycardia, Tics, Urticaria, Erectile Disorder, Increased urination, Blunted affect, Impaired growth in children

Rare side effects

Some information in this article or section has not been verified and may not be reliable.
Please check for inaccuracies, and modify and cite sources as needed.

Rare side effects of Adderall used as prescribed include:Amphetamine psychosis^{[citation
needed]}, high blood pressure, tourettism^{[citation
needed]}, cardiomyopathy^{[citation
needed]}, and hair loss^{[citation
needed]}.

Contraindications

Using any amphetamine, (including Adderall, methamphetamine or MDMA) within 1-2 weeks of taking a monoamine oxidase inhibitor (MAOI) can cause a potentially fatal condition known as serotonin syndrome.

Performance-enhancing use

Because Adderall uses amphetamine stimulants to help the user concentrate for extended periods of time, many students today request Adderall from doctors in order to use it as a study aid. Thus, it is increasingly popular on college campuses. The largest benefit to students, however, is Adderall's ability to give students the power to focus on and learn what would usually be uninteresting material. Because of the appetite-suppressing properties of amphetamines, it is also sought after by those wishing to lose weight. Another less common use for students is to take Adderall before or during a night of heavy drinking in order to remain alert and active despite being intoxicated.

Research done by the National Institute of Drug Abuse (NIDA) shows the more competitive the college, the higher the incidence of stimulant use. An article published stated the findings of a nationwide survey of thousands of college students[3]. The findings of this past April 2006 survey shows 5.9% use rates among the more competitive campuses, compared to 1.3% use rates among less competitive campuses. Breaking down the use pattern even further, this same sample done by NIDA reveals whites were more likely to use stimulants compared to African Americans and Asians, at rates of 4.9%, 1.6%, and 1.3% respectively. Further, students with lower grade point averages of B’s or below use stimulants at a rate of 5.2%, compared to students earning B+ or above who use this medication at rates of only 3.3%. This research also specifically identified that students involved in sororities or fraternities use stimulants at a much higher rate of 8.6% compared to nonmembers who reported use at rates of only 3.3% (Whitten, 6).

Another major concern about the use of Adderall among college students is the psychological dependence that may cause students to lose faith in their own ability to perform well and the dependence on the advantageous effects of stimulant medication. Jackie Kurta, an Alcohol and Drug Specialist at UC Santa Barbara’s Student Heath Services states, “Students start out taking study drugs one time to study. The drugs work so well that the students begin to lose confidence in their own abilities to study without them,” (Hirschey).

The black market price of Adderall varies widely, and is often between $1.50 to $10 per pill (size also varies from 5 to 30mg.) In some cases, pills may sell for as little as $.20 or as much as $25.

Aside from being used by college students as a study aide, Adderall has been used as an off label drug for weight loss. Adderall’s side effect of weight loss and appetite suppression is a desired result for those trying to lose weight. It is administered as part of a “cocktail” of other off label prescription drugs that have side effects used to treat obesity. There have not been any scientific studies performed to evaluate the effectiveness of this form of treatment and is viewed a very risky and potentially dangerous way to shed pounds. (http://www.msnbc.msn.com/id/15385195/)

Government warnings

On February 9, 2005, Health Canada suspended all sales of Adderall XR after data collected by manufacturer Shire Pharmaceuticals linked the drug to 12 sudden deaths in American children between the years 1999 to 2003. [4]. Further research, however, found little data suggesting use of Adderall resulted in an increased risk of cardiac defect. Of the twelve sudden deaths positively linked to pediatric Adderall users during the four year period, five had known pre-existing cardiac conditions, one died after strenuous exercise in 110 degree heat and two had levels suggestive of an overdose. Given the more than 37,000,000 prescriptions for Adderall filled during the four years, the US Food and Drug Administration could find no increased risk of sudden death among Adderall users beyond the normal rate of the general population. [5], [6] In August, 2005, Health Canada followed the committee report of three independent physicians and lifted the ban on Adderall XR. [7], [8] Given that persons with AD/HD are a high risk group, it has been suggested that stimulant medications for persons with AD/HD will actually result in lower incidence of premature death. [9]

advise against the use of Adderall in those persons with pre-existing cardiac or mental illnesses. They also suggest against its use in persons who have a history of drug abuse. [10] Although FDA safety advisors voted 8 to 7 to issue a Black Box Warning, the FDA's pediatric advisory committee refused to give the drug its most severe black box warning in March, 2006. [11] A Black Box Warning regarding amphetamine abuse potential is in place, however.

Manufacturers

Adderall is manufactured by Shire Pharmaceuticals and is distributed by Catalytica Pharmaceuticals Inc. of Greenville, North Carolina. Generic equivalents (known to pharmacists as "amphetamine salts," "mixed amphetamines," or simply "amphetamines," among other things) are also distributed in the United States by Barr Pharmaceuticals, Mallinckrodt Pharmaceuticals, Eon Labs and Ranbaxy Laboratories.

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor XR or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor XR is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.)

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

SIDE EFFECTS

The information included in the Adverse Findings Observed in Short-Term,

Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR , and on data up to 12 weeks from a pool of two controlled clinical trials in Social Anxiety Disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (the immediate release formulation of venlafaxine) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection (see also WARNINGS and PRECAUTIONS).

Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR

Adverse Events Associated with Discontinuation of Treatment

Approximately 11% of the 357 patients who received Effexor XR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 17% of the 277 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 274 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for either indication) are shown in Table 2.

Table 2 : Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials¹

Percentage of Patients Discontinuing Due to Adverse Event

Adverse Event

Major Depressive Disorder Indication²

GAD Indication^3,4

Social Anxiety Disorder Indication

Effexor XR n = 357

Placebo n = 285

Effexor XR n = 1381

Placebo n = 555

Effexor XR n = 277

Placebo n = 274

Body as a Whole

Asthenia
--

--

3%

<1%

1%

<1%

Headache
--

--

--

--

2%

<1%

Digestive System

Nausea
4%

<1%

8%

<1%

4%

0%

Anorexia
1%

<1%

--

--

--

--

Dry Mouth
1%

0%

2%

<1%

--

--

Vomiting
--

--

1%

<1%

--

--

Nervous System

Dizziness
2%

1%

--

--

2%

0%

Insomnia
1%

<1%

3%

<1%

3%

<1%

Somnolence
2%

<1%

3%

<1%

2%

<1%

Nervousness
--

--

2%

<1%

--

--

Tremor
--

--

1%

0%

--

--

Anxiety
--

--

--

--

1%

<1%

Skin

Sweating
--

--

2%

<1%

1%

0%

Urogenital System

Impotence⁵
--

--

--

--

3%

0%

¹Two of the major depressive disorder studies were flexible dose and one was fixed dose. Four of the GAD studies were fixed dose and one was flexible dose. Both of the Social Anxiety Disorder studies were flexible dose.

² In U.S. placebo-controlled trials for major depressive disorder, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 192], % Placebo [n = 202]): hypertension (1%,<1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%).

³ In two short-term U.S. placebo-controlled trials for GAD, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 476]), % Placebo [n = 201]: headache (4%, <1%); vasodilatation (1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormal vision (1%, 0%).

⁴ In long-term placebo-controlled trials for GAD, the following was also a common event leading to discontinuation and was considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%).

⁵ Incidence is based on the number of men (Effexor XR = 158, placebo = 153).

Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients

Tables 3, 4, and 5 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), and of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Commonly Observed Adverse Events from Tables 3, 4, and 5:

Major Depressive Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder (Table 3): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning.

Generalized Anxiety Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 4): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating.

Social Anxiety Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 2 placebo-controlled trials for the Social Anxiety Disorder indication (Table 5): Asthenia, gastrointestinal complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and abnormal vision.

Table 3 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Patients with Major Depressive Disorder^1,2

% Reporting Event

Body System

Effexor XR

Placebo

Preferred Term

(n = 357)

(n = 285)

Body as a Whole

Asthenia
8%

7%

Cardiovascular System

Vasodilatation³
4%

2%

Hypertension
4%

1%

Digestive System

Nausea
31%

12%

Constipation
8%

5%

Anorexia
8%

4%

Vomiting
4%

2%

Flatulence
4%

3%

Metabolic/Nutritional

Weight Loss
3%

0%

Nervous System

Dizziness
20%

9%

Somnolence
17%

8%

Insomnia
17%

11%

Dry Mouth
12%

6%

Nervousness
10%

5%

Abnormal Dreams4
7%

2%

Tremor
5%

2%

Depression
3%

<1%

Paresthesia
3%

1%

Libido Decreased
3%

<1%

Agitation
3%

1%

Respiratory System

Pharyngitis
7%

6%

Yawn
3%

0%

Skin

Sweating
14%

3%

Special Senses

Abnormal Vision⁵
4%

<1%

Urogenital System

Abnormal Ejaculation (male)^6,7
16%

<1%

Impotence⁷
4%

<1%

Anorgasmia (female)^8,9
3%

<1%

¹ Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with Effexor XR, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis.

² <1% indicates an incidence greater than zero but less than 1%.

³ Mostly “hot flashes.”

⁴ Mostly “vivid dreams,” “nightmares,” and “increased dreaming.”

⁵ Mostly “blurred vision” and “difficulty focusing eyes.”

⁶ Mostly “delayed ejaculation.”

⁷ Incidence is based on the number of male patients.

⁸Mostly “delayed orgasm” or “anorgasmia.”

⁹ Incidence is based on the number of female patients.

Table 4: Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in GAD Patients^1,2

% Reporting Event

Body System

Effexor XR

Placebo

Preferred Term
(n = 1381)

(n = 555)

Body as a Whole

Asthenia
12%

8%

Cardiovascular System

Vasodilatation³
4%

2%

Digestive System

Nausea
35%

12%

Constipation
10%

4%

Anorexia
8%

2%

Vomiting
5%

3%

Nervous System

Dizziness
16%

11%

Dry Mouth
16%

6%

Insomnia
15%

10%

Somnolence
14%

8%

Nervousness
6%

4%

Libido Decreased
4%

2%

Tremor
4%

<1%

Abnormal Dreams⁴
3%

2%

Hypertonia
3%

2%

Paresthesia
2%

1%

Respiratory System

Yawn
3%

<1%

Skin

Sweating
10%

3%

Special Senses

Abnormal Vision⁵
5%

<1%

Urogenital System

Abnormal Ejaculation^6,7
11%

<1%

Impotence⁷
5%

<1%

Orgasmic Dysfunction (female)^8,9
2%

0%

¹ Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency.

² <1% means greater than zero but less than 1%.

³ Mostly “hot flashes.”

⁴Mostly “vivid dreams,” “nightmares,” and “increased dreaming.”

⁵ Mostly “blurred vision” and “difficulty focusing eyes.”

⁶ Includes “delayed ejaculation” and “anorgasmia.”

⁷ Percentage based on the number of males (Effexor XR = 525, placebo = 220).

⁸ Includes “delayed orgasm,” “abnormal orgasm,” and “anorgasmia.”

⁹ Percentage based on the number of females (Effexor XR = 856, placebo = 335).

Table 5 : Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Social Anxiety Disorder Patients^1,2

% Reporting Event

Body System
Effexor XR

Placebo

Preferred Term
(n = 277)

(n = 274)

Body as a Whole

Headache
34%

33%

Asthenia
17%

8%

Flu Syndrome
6%

5%

Accidental Injury
5%

3%

Abdominal Pain
4%

3%

Cardiovascular System

Hypertension
5%

4%

Vasodilatation³
3%

1%

Palpitation
3%

1%

Digestive System

Nausea
29%

9%

Anorexia⁴
20%

1%

Constipation
8%

4%

Diarrhea
6%

5%

Vomiting
3%

2%

Eructation
2%

0%

Metabolic/Nutritional

Weight Loss
4%

0%

Nervous System

Insomnia
23%

7%

Dry Mouth
17%

4%

Dizziness
16%

8%

Somnolence
16%

8%

Nervousness
11%

3%

Libido Decreased
9%

<1%

Anxiety
5%

3%

Agitation
4%

1%

Tremor
4%

<1%

Abnormal Dreams⁵
4%

<1%

Paresthesia
3%

<1%

Twitching
2%

0%

Respiratory System

Yawn
5%

<1%

Sinusitis
2%

1%

Skin

Sweating
13%

2%

Special Senses

Abnormal Vision⁶
6%

3%

Urogenital System

Abnormal Ejaculation^7,8
16%

1%

Impotence⁸
10%

1%

Orgasmic Dysfunction^9,10
8%

0%

¹ Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: back pain, depression, dysmenorrhea, dyspepsia, infection, myalgia, pain, pharyngitis, rash, rhinitis, and upper respiratory infection.

² <1% means greater than zero but less than 1%.

³ Mostly “hot flashes.”

⁴ Mostly “decreased appetite” and “loss of appetite.”

⁵ Mostly “vivid dreams,” “nightmares,” and “increased dreaming.”

⁶ Mostly “blurred vision.”

⁷ Includes “delayed ejaculation” and “anorgasmia.”

⁸ Percentage based on the number of males (Effexor XR = 158, placebo = 153).

⁹ Includes “abnormal orgasm” and “anorgasmia.”

¹⁰ Percentage based on the number of females (Effexor XR = 119, placebo = 121).

Vital Sign Changes

Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 4 beats per minute, compared with an increase of 1 beat per minute for placebo. (See the Sustained Hypertension section of WARNINGS for effects on blood pressure.)

In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo.

Laboratory Changes

Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 11.4 mg/dL compared with a mean final decrease of 2.2 mg/dL for placebo.

Patients treated with Effexor tablets (the immediate-release form of venlafaxine) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ³ 50 mg/dL from baseline and to a value ³261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ³ 50 mg/dL from baseline and to a value 261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation).

ECG Changes

In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo.

(See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)

Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR

During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 3, 4, and 5 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis.

Cardiovascular system - Frequent: migraine, postural hypotension, tachycardia;

Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor.

Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration.

Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.

Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura.

Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.

Musculoskeletal system - Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.

Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis.

Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.

Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae.

Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis.

Urogenital system - Frequent: metrorrhagia,* prostatic disorder (prostatitis and enlarged prostate),* urination impaired, vaginitis*; Infrequent: albuminuria, amenorrhea,* cystitis, dysuria, hematuria, leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage*; Rare: abortion,* anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.*

*Based on the number of men and women as appropriate.

Postmarketing Reports

Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly).

There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance.

Physical and Psychological Dependence

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.

Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION).

While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior).

DRUG INTERACTIONS

As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Alcohol

A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.

Cimetidine

Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C_max) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

Diazepam

Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.

Haloperidol

Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol C_max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t½) was unchanged. The mechanism explaining this finding is unknown.

Lithium

The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below).

Drugs Highly Bound to Plasma Proteins

Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Drugs that Inhibit Cytochrome P450 Isoenzymes

CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.

The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied.

Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce simultaneous inhibition of these two enzyme systems.

Drugs Metabolized by Cytochrome P450 Isoenzymes

CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C_max, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC’s increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.

Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C_max. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.

CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.

CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.

CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS and WARNINGS.

CNS-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above).

Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors (SRIs), or lithium.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment.

Venlafaxine

Venlafaxine hydrochloride is a prescription antidepressant first introduced by Wyeth in 1993. It belongs to class of antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRI). As of August 2006, generic venlafaxine is available in the United States, and as of December 2006, generic venlafaxine is available in Canada. It was previously available only under the brand names Effexor and Effexor XR. It is also available in the UK under both names.

Contents

[hide]

1 Trade names

2 Description of compound

3 Mechanism of action

3.1 Pharmacokinetics

4 Indications

4.1 Approved

4.2 Off-label / investigational uses

5 Contraindications

5.1 Pregnancy, labor and delivery

6 Dose range

7 Available forms

7.1 Venlafaxine Extended Release (XR)

8 Effectiveness

9 Adverse effects

9.1 Suicide Ideation/Risk

9.2 Serotonin Syndrome

9.3 Common side effects

9.4 Less common to rare side-effects

9.5 Dose dependency of adverse events

9.6 Physical and Psychological Dependency

10 Overdose

10.1 Management of Overdosage

11 Footnotes

12 External links

12.1 Drug information

12.2 Industry pages

12.3 Patient experiences

12.4 Chemical data

Trade names

Venlafaxine is marketed under the tradenames, Effexor^®, Efectin^®, Effexor XR^®, and Efectin ER^®.

Description of compound

The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride and it has the empirical formula of C₁₇H₂₇NO₂. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the analgesic tramadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or reversible inhibitors of monoamine oxidase (RIMAs).^[1]

Mechanism of action

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.^[2]^[3] It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitter in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline) Additionally, in high doses it weakly inhibits the reuptake of dopamine,^[4] 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).

Pharmacokinetics

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. 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.^[5] 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.^[6]

Indications

Approved

Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, and panic disorder in adults only. It is also used for other general depressive disorders.^[5]

Off-label / investigational uses

Many doctors are starting to prescribe venlafaxine "off label" for the treatment of diabetic neuropathy (in a similar manner to duloxetine) and migraine prophylaxis (in some people, however, venlafaxine can exacerbate or cause migraines). Studies have shown venlafaxine's effectiveness for these conditions.^[7]^[8] It has also been found to reduce the severity of 'hot-flashes' in menopausal women.^[9]^[10]

Substantial weight loss in patients with major depression, generalized anxiety disorder, and social phobia has been noted, but the manufacturer does not recommend use as an anorectic either alone or in combination with phentermine or other amphetamine-like drugs.^[5]

Venlafaxine is not approved for the treatment of depressive phases of bipolar disorder; this has some potential danger as venlafaxine can induce mania, mixed states, rapid cycling and/or psychosis in some bipolar patients, particularly if they are not also being treated with a mood stabilizer.^[5] Venlafaxine is perhaps one of the most likely of all modern antidepressants to trigger manic and hypomanic states.

Contraindications

Venlafaxine is not recommended in patients hypersensitive to venlafaxine. 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. Caution should also be used in those with a seizure disorder. Venlafaxine is not approved for use in children or adolescents.^[5] 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.^[11]

Pregnancy, labor and delivery

There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed.^[5] Prospective studies have not shown any statistically significant congenital malformations.^[12] There have, however, been some reports of effects on new born infants.^[13] In view of the possibility of severe discontinuation syndrome and the difficulties this presents, use of venlafaxine for pregnant women is not generally indicated. The FDA has asked the sponsors of all SSRIs to change prescribing information to describe the potential risk for persistent pulmonary hypertension (PPHN) as July 19, 2006.

Dose range

Prescribed dosages are typically in the range of 75 to 225 mg per day, but higher dosages are sometimes used for the treatment of severe or treatment-resistant depression. Venlafaxine is sometimes prescribed in 37.5 mg per day dosages in patients with anxiety. Low doses only work on the serotonin reuptake mechanism (presumed defective in those with anxiety) therefore avoiding the anxiety inducing effects of norepinephrine reuptake experienced at higher doses. Because of its relatively short half-life of 5 hours, venlafaxine should be administered in divided dosages throughout the day. The extended release version (largely manufactured on spheronization equipment) eliminates this problem and has largely replaced the original in use.

An Effexor XR^® 75 mg Capsule

Available forms

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 Extended Release (XR)

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 of time 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.^[14]

Effectiveness

Venlafaxine is an effective anti-depressant for many persons; however, it seems to be especially effective for those with treatment-resistant depression. Some of these persons have taken two or more antidepressants prior to venlafaxine with no relief. Patients suffering with severe long-term depression typically respond better to venlafaxine than other drugs. However, venlafaxine has been reported to be more difficult to discontinue than other anti-depressants. In addition, a September 2004 Consumer Reports study ranked venlafaxine as the most effective among six commonly prescribed antidepressants. Like most psychiatric medications, however, the results of such studies alone should not be relied upon by potential patients, as responses to psychiatric medications can vary significantly from individual to individual.

Adverse effects

As with most antidepressants, lack of sexual desire is a common side effect. Venlafaxine can raise blood pressure at high doses, so it is usually not the drug of choice 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.

Suicide Ideation/Risk

A Black Box Warning has been issued with Effexor and with other SSRI and SNRI anti-depressants advising of risk of suicide. Thoughts of suicide (suicide ideation) as potential risk of suicide as shown in studies by Wyeth and reported on their datasheet for Effexor were twice that of placebo (4% compared to 2%, however, no suicides occurred in these trials).^[5] The black box warnings advise physicians to carefully monitor patients for suicide risk at start of usage and whenever the dosage is changed. There is an additional risk if a physician misinterprets patient expression of adverse effects such as panic or akathisia as symptoms of worsening depression rather than effects of the medication and increases dose. Assessment of patient history and comorbid risk factors such as drug abuse are recommended when evaluating the safety of venlafaxine for individual patients. These cautions are emphasized in Wyeth's information sheet with special precautions if prescribed to children. The extent of this effect and the actual risk are not known as studies may exclude individuals with higher risk.

In the UK, one study evaluated whether risk factors for suicide were more prevalent among patients prescribed venlafaxine than patients prescribed other antidepressants. Results showed patients prescribed venlafaxine were more likely to have attempted suicide in the previous year, although it was concluded that venlafaxine had been selectively prescribed to a patient population with a higher burden of suicide risk factors to begin with, and that this might have led to a higher future risk of suicide independent of any drug effect. Studies with baseline data are required to determine the actual risk with venlafaxine.^[15]

Serotonin Syndrome

Another risk is Serotonin syndrome. This is a rare, however serious side effect that can be caused by interactions with other Central Nervous System depressant drugs and is potentially fatal.^[16] This risk necessitates clear information to patients and proper medical history. For example, the drug abuse by at risk patients of certain non-prescription drugs can cause this serious effect and emphasizes the importance of good medical history sharing between General Practitioners and Psychiatrists as both may prescribe Venlafaxine. Involvement of family in awareness of risk factors is highlighted in Wyeth information sheets on Effexor.

Common side effects

Nausea

Ongoing Irritable Bowel Syndrome

Dizziness

Fatigue

Insomnia

Vertigo

Dry mouth

Sexual dysfunction

Sweating

Vivid dreams

Increased blood pressure

Electric shock-like sensations also called "Brain shivers"

Increased anxiety at the start of treatment

Akathisia (Agitation)

Less common to rare side-effects

Cardiac arrhythmia

Increased serum cholesterol

Gas or stomach pain

Abnormal vision

Nervousness, agitation or increased anxiety akathisia

Panic Attacks

Depressed feelings

Suicidal thoughts suicidal ideation

Confusion

Neuroleptic malignant syndrome

Loss of appetite

Constipation

Tremor

Drowsiness

Allergic skin reactions

External bleeding

Serious bone marrow damage (thrombocytopenia, agranulocytosis)

Hepatitis

Pancreatitis

Seizure

Tardive dyskinesia

Difficulty swallowing

Psychosis

Hair Loss

Hostility

Activation of mania/hypomania.

Weight Loss (of concern when treating anorexic patients)

Weight gain (effect not clear, but of concern when treating young women who may have Body Dysmorphic Disorder).

Homicidal Thoughts Homicidal Ideations

Aggression

Depersonalization

Psychosis

Visual Hallucinations

Swollen and/or bleeding gums

Dose dependency of adverse events

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.^[5]

Physical and Psychological Dependency

Main article: SSRI discontinuation syndrome#Discontinuation of Venlafaxine

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.^[5]

Notwithstanding these in-vitro and non-human research findings, some patients using venlafaxine may become dependent on this drug. This is especially noted if a patient misses a dose, but can also occur when reduction of dosage is done with a doctor's care. This may result in experiencing withdrawal symptoms described as severe discontinuation syndrome. The high risk of withdrawal symptoms may reflect venlafaxines short half-life.^[17] Missing even a single dose can induce discontinuation effects in some patients.^[6] Discontinuation is similar in nature to those of SSRIs such as Paroxetine (Paxil® or Seroxat®). Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms.^[18]

As the drug has direct impact on mood (i.e. anti-depressant), many users who have suffered the effects of attempted withdrawal from this drug define their dependency on the drug also as being addicted.^[17] Although many other drugs can cause withdrawal symptoms which are not associated with addiction or dependence, for example, anticonvulsants, beta-blockers, nitrates, diuretics, centrally acting antihypertensives, sympathomimetics, heparin, tamoxifen, dopaminergic agents, antipsychotics, and lithium,^[17] addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.^[19] An internet petition of effexor users and family members with signatories in the tens of thousands (at the time of writing) describes the impact of discontinuation of this drug. It is therefore important that prescribing doctors explain the details of this drug to patients with care.

Overdose

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.^[20] Venlafaxines 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.^[1] Deaths have been reported following large doses.^[21]^[22]

On May 31st 2006, The Medicines and Healthcare Products Regulatory Agency (MHPRA) UK has concluded its review into all the latest safety evidence relating to venlafaxine particularly looked at the risks associated with overdose. The advice are, the need for specialist supervision in those severely depressed or hospitalized patients who need doses 300mg or more; cardiac contra-indications are more targeted towards high risk groups; patients with uncontrolled hypertension should not take venlafaxine, and blood pressure monitoring is recommended for all patients; and updated advice on possible drug interactions. ^[23]

On October 17, 2006 Wyeth and the FDA notified healthcare professionals of revisions to the Overdosage/Human Experience section of the prescribing information for Effexor (venlafaxine), indicated for treatment of major depressive disorder. In postmarketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.^[24]

Management of Overdosage

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.^[25]

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Vicodin

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