Re: Link to the ANCP report Effexor maker admits to youth suicidal ideation

January 25, 2004

Dear

As you said " Hi, I'm new................. "

*********** You are welcome to join in our debate

" I haven't read much of the board yet,........... "

READ THIS PLEASE and COMMENT upon the info provided by the DRUG maker

respectfully morse

Effexor maker (Wyeth) ADMITS to PAEDIATRIC suicidal ideation in

it's OWN DATA files

http://www.medsafe.govt.nz/profs/Datasheet/e/Efexorxrcap.htm

" Paediatric Use

Safety and effectiveness in individuals below 18 years of age have

not been established. Efexor-XR should not be used in such patients.

As with adults, decreased appetite, weight loss, increased blood

pressure and increased serum cholesterol have been observed in

children and adolescents aged 6 to 17 years.

In paediatric clinical trials, there were increased reports of

hostility and, especially in major depression, suicide-related

adverse events such as suicidal ideation and self-harm.............. "

Data Sheet

EFEXOR®-XR

(Venlafaxine Hydrochloride)

Modified Release Capsules

NAme of drug

EFEXOR-XR

Venlafaxine hydrochloride 75 mg and 150 mg modified release capsules.

DESCRIPTION

EFEXOR-XR capsules are an extended-release formulation, which

release the active constituent, venlafaxine hydrochloride, from

spheroids within the capsule. Drug release is controlled by

diffusion through the coating membrane on the spheroids and is not

pH dependent. Two strengths of EFEXOR-XR capsules are available

containing either 75 mg or 150 mg of venlafaxine (as hydrochloride).

Venlafaxine hydrochloride is chemically defined (R/S)-1-[(2-

dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride.

It is a white to off-white crystalline solid with a solubility of

572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium

chloride). Its molecular weight is 313.87.

Other ingredients are cellulose-microcrystalline, ethylcellulose,

hypromellose, gelatin, red iron oxide CI 77491, yellow iron oxide CI

77492, titanium dioxide and talc purified.

PHARMACOLOGY

Actions

Venlafaxine is a structurally novel antidepressant for oral

administration; it is chemically unrelated to tricyclic,

tetracyclic, or other available antidepressant agents.

The antidepressant action of venlafaxine in humans is believed to be

associated with its potentiation of neurotransmitter activity in the

central nervous system. Preclinical studies have shown that

venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV),

are potent inhibitors of serotonin and noradrenaline reuptake, and

also weakly inhibit dopamine reuptake. Venlafaxine is a racemate.

The R-enantiomer is relatively more potent than the S-enantiomer

with regard to inhibition of noradrenaline reuptake; the S-

enantiomer is more potent regarding inhibition of serotonin

reuptake. Both enantiomers are more potent on serotonin compared to

noradrenaline reuptake. The enantiomers of ODV also inhibit both

noradrenaline and serotonin reuptake, with the R-enantiomer being

more potent. Venlafaxine and its major metabolite appear to be

equipotent with respect to their overall action on neurotransmitter

re-uptake and receptor binding. Studies in animals show that

tricyclic antidepressants may reduce ß-adrenergic receptor

responsiveness following chronic administration. In contrast,

venlafaxine and ODV reduce ß-adrenergic responsiveness after both

acute (single dose) and chronic administration.

Venlafaxine has no significant affinity for rat brain muscarinic, H1-

histaminergic or a1-adrenergic receptors in vitro. Pharmacological

activity at these receptors is potentially associated with various

sedative, cardiovascular, and anticholinergic effects seen with

other psychotropic drugs. Venlafaxine does not possess monoamine

oxidase (MAO) inhibitory activity.

In vitro studies revealed that venlafaxine has virtually no affinity

for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-

aspartic acid (NMDA) receptors. Venlafaxine also does not produce

noradrenaline release from brain slices. It has no significant

central nervous system (CNS) stimulant activity in rodents. In

primate drug discrimination studies, venlafaxine showed no

significant stimulant or depressant abuse liability.

Pharmacokinetics

Steady-state concentrations of venlafaxine and ODV are attained

within 3 days of oral multiple-dose therapy. Venlafaxine and ODV

exhibited linear kinetics over the dose range of 75 to 450 mg/day.

Mean±SD steady-state plasma clearance of venlafaxine and ODV is

1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-

life is 5±2 and 11±2 hours, respectively; and apparent (steady-

state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg,

respectively.

Absorption

On the basis of mass balance studies, at least 92% of a single oral

dose of venlafaxine is absorbed, indicating that absorption of

venlafaxine is nearly complete. However, the presystemic metabolism

of venlafaxine (which primarily forms the active metabolite, ODV)

reduces the absolute bioavailability of venlafaxine to 42%±15%.

After administration of EFEXOR-XR (150 mg q24 hours), the peak

plasma concentrations (Cmax) of venlafaxine (150 ng/mL) and ODV (260

ng/mL) were attained within 6.0±1.5 and 8.8±2.2 hours, respectively.

The rate of absorption of venlafaxine from the EFEXOR-XR capsule is

slower than its rate of elimination. Therefore, the apparent

elimination half-life of venlafaxine following administration of

EFEXOR-XR (15±6 hours) is actually the absorption half-life instead

of the true disposition half-life (5±2 hours) observed following

administration of an immediate-release tablet.

When equal doses of venlafaxine, administered either as an immediate-

release tablet taken in divided doses or as a modified-release

capsule, were taken once a day, the exposure (AUC, area under the

concentration curve) to both venlafaxine and ODV was similar for the

two treatments, and the fluctuation in plasma concentrations was

slightly lower following treatment with the EFEXOR-XR capsule.

Therefore, the EFEXOR-XR capsule provides a slower rate of

absorption, but the same extent of absorption (i.e., AUC), as the

venlafaxine immediate-release tablet.

No accumulation of venlafaxine or ODV has been observed during

chronic administration in healthy subjects.

Distribution

The degree of binding of venlafaxine to human plasma proteins is 27%

±2% at concentrations ranging from 2.5 to 2215 ng/mL, and the degree

of ODV binding to human plasma proteins is 30%±12% at concentrations

ranging from 100 to 500 ng/mL. Protein-binding-induced drug

interactions with concomitantly administered venlafaxine are not

expected. Following intravenous administration, the steady-state

volume of distribution of venlafaxine is 4.4±1.9 L/kg, indicating

that venlafaxine distributes well beyond the total body water.

Metabolism

Following absorption, venlafaxine undergoes extensive pre-systemic

metabolism in the liver. The primary metabolite of venlafaxine is

ODV, but venlafaxine is also metabolised to N-desmethylvenlafaxine,

N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro

studies indicate that the formation of ODV is catalysed by CYP2D6

and that the formation of N-desmethylvenlafaxine is catalysed by

CYP3A3/4. The results of the in vitro studies have been confirmed in

a clinical study with subjects who are CYP2D6-poor and -extensive

metabolisers. However, despite the metabolic differences between the

CYP2D6-poor and -extensive metabolisers, the total exposure to the

sum of the two active species (venlafaxine and ODV) was similar in

the two metaboliser groups. Therefore, CYP2D6-poor and -extensive

metabolisers can be treated with the same regimen of EFEXOR-XR (see

Interactions with Other Drugs, CYP2D6 Inhibitors).

Excretion

Approximately 87% of a venlafaxine dose is recovered in the urine

within 48 hours after a single radio-labelled dose as either

unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV

(26%), or other minor inactive metabolites (27%), and 92% of the

radioactive dose is recovered within 72 hours. Therefore, renal

elimination of venlafaxine and its metabolites is the primary route

of excretion.

Food-Drug Interactions

Administration of EFEXOR-XR with food has no effect on the

absorption of venlafaxine or on the subsequent formation of ODV.

Subject age and sex do not significantly affect the pharmacokinetics

of venlafaxine. A 20% reduction in clearance was noted for ODV in

subjects over 60 years old; this was probably caused by the decrease

in renal function that typically occurs with aging.

In some patients with compensated hepatic cirrhosis, the

pharmacokinetic disposition of both venlafaxine and ODV was

significantly altered. The reduction in both the metabolism of

venlafaxine and elimination of ODV resulted in higher plasma

concentrations of both venlafaxine and ODV.

In patients with moderate to severe impairment of renal function,

the total clearance of both venlafaxine and ODV was reduced, and t½

was prolonged. The reduction in total clearance was most pronounced

in subjects with creatinine clearance less than 30 mL/min.

Clinical Trials

Use in Major Depression

Three double blind, placebo controlled trials, of up to 12 weeks

duration, have examined the clinical efficacy of EFEXOR-XR in the

treatment of major depression. One of these studies also

incorporated an active comparator, paroxetine. These studies showed

EFEXOR-XR to have greater efficacy than both placebo and paroxetine

in reducing depression.

Use in Generalised Anxiety Disorder

Five placebo-controlled trials were conducted to evaluate the

efficacy of EFEXOR-XR in the treatment of anxiety. Two trials were

eight-week studies, utilizing Efexor-XR doses of 75 mg, 150 mg and

225 mg/day and of 75 mg and 150 mg/day. In one of these, buspirone

was found not to be significantly different to placebo or to Efexor-

XR. However, Efexor-XR was found to be superior to placebo. Two

other trials were the first eight-weeks of two long term studies,

utilizing Efexor-XR doses of 75 mg-225 mg/day and of 37.5 mg, 75 mg

and 150 mg/day.

Four studies demonstrated superiority of Efexor-XR over placebo on

at least five of the following efficacy scales: HAM-A total score,

the HAM-A psychic anxiety factor, the Hospital Anxiety and

Depression (HAD) anxiety subscale, and the CGI severity of illness

scale, as well as the HAM-A anxious mood and tension item. Two of

these four studies continued for up to six months. These two

studies, which utilized Efexor-XR doses of 75 mg-225 mg/day and 37.5

mg, 75 mg and 150 mg/day demonstrated superiority of Efexor-XR over

placebo on the HAM-A total score, HAM-A psychic anxiety factor, the

HAD anxiety factor, and the CGI severity of illness scale, as well

as the HAM-A anxious mood item.

The fifth trial was a short-term (8-week) comparison of the efficacy

of 2 fixed doses of EFEXOR-XR (75 mg and 150 mg) with placebo and

diazepam followed by a comparison of the long-term (6-month)

efficacy of EFEXOR-XR and placebo in the prevention of relapse. The

most important results were the primary efficacy variables at week 8

using an LOCF analysis. These demonstrated no significant

differences between either venlafaxine and placebo, or diazepam and

placebo for any of the primary efficacy variables. In view of this

failure to demonstrate any effectiveness of either venlafaxine or

diazepam over placebo, the long-term outcomes of this study are not

of clinical or theoretical value. In conclusion, this study showed

no anxiolytic effect of either diazepam or placebo in the short-term

(8 week phase).

Baseline and Final Mean HAM-A Total and CGI Severity Scores for

Placebo-Controlled GAD Studies

Study Number

----------- HAM-A Total-----------

----------- CGI Severity ---------

Treatment

n

Baseline

Final

n

Baseline

Final

210 (8-week study)

Placebo 96

24.1

14.7

96

4.4

3.2

Venlafaxine XR (mg)

75

86

24.7

13.5

86

4.5

3.0

150

81

24.5

12.3

81

4.5

2.9

225

86

23.6

11.9

86

4.4

2.8

214 (8-week study)

Placebo

98

23.7

15.4

98

4.3

3.3

Venlafaxine XR (mg)

75

87

23.7

13.0

87

4.2

2.8

150

87

23.0

13.6

87

4.2

3.0

Buspirone

93

23.8

14.3

93

4.2

3.2

218 (6-month study)

Placebo

123

24.9

16.2

123

4.4

3.5

Venlafaxine XR (mg)

75-225

115

25.0

11.6

115

4.4

2.7

377 (8-week period)

Placebo

96

27.7

15.1

89

4.8

3.2

Venlafaxine XR (mg)

75

181

28.0

12.8

160

4.9

2.9

150

169

28.0

14.2

146

4.9

3.1

epam

89

28.4

13.5

79

4.8

2.9

378 (6-month study)

Placebo

129

26.7

15.6

129

4.6

3.2

Venlafaxine XR (mg)

37.5

138

26.6

12.6

138

4.4

2.6

75

130

26.3

10.4

129

4.4

2.4

150

131

26.3

9.5

131

4.6

2.2

Depression Relapse/Recurrence

A long-term study of depressed outpatients who had responded to

EFEXOR-XR during an initial 8-week open-label treatment phase and

were randomly assigned to continuation on EFEXOR-XR or placebo for 6

months demonstrated a significantly lower relapse rate for patients

taking EFEXOR-XR compared with those on placebo.

In a second long-term study, outpatients with a history of recurrent

depression who had responded to EFEXOR (the immediate-release form

of venlafaxine) by 8 weeks and maintained improvement during an

initial 6-month open-label treatment phase were randomly assigned to

maintenance therapy on EFEXOR or placebo for 12 months.

Significantly fewer patients taking EFEXOR compared with those on

placebo had a reappearance of depression.

Social Anxiety Disorder

The efficacy of Efexor-XR as a treatment for social anxiety disorder

(also known as social phobia) was established in four double-blind,

parallel-group, 12-week, multi-centre, placebo-controlled, flexible-

dose studies and one double-blind, parallel-group, 6-month,

fixed/flexible-dose study in adult outpatients meeting DSM-IV

criteria for Social Anxiety Disorder. Patients received doses in a

range of 75-225 mg/day. Efficacy was assessed with the Liebowitz

Social Anxiety Scale (LSAS). The LSAS measures the relationship of

impairment because of social anxiety disorder symptoms by evaluating

a patient's fear and avoidance in a broad range of situations (i.e.,

13 performance and 11 social interaction situations). Psychometric

studies have shown the LSAS to be a valid and reliable measure of

social anxiety.1 The LSAS scale has also been shown to be sensitive

to differences between active and placebo treatments.2

The results of these trials are presented in the table below. In

these five trials, Efexor-XR was significantly more effective than

placebo on change from baseline to endpoint on the LSAS total score.

Summary of Results for Primary Efficacy Variable in ITT Patients at

Final On-Therapy Visit: 12 week and 6 month

Variable

Study Number

No. of Patients

Raw baseline Score

Adjusted Final On-therapy Score

Adjusted Mean Change from Baseline

p-value vs Placebo

Treatment Group

Short-term (12 week) Studies

LSAS

Study 1

Placebo

138

86.7

69.0

-19.9

Venlafaxine XRa 133 91.1 57.8 -31.0 <0.001

Study 2b

Placebo 135 87.4 66.9 -22.1

Venlafaxine XRa

126

90.8

56.3

-32.8

0.003

Study 3

Placebo 132 83.6 64.5 -19.1

Venlafaxine XRa 129 83.2 47.6 -36.0 <0.001

Paroxetinec

128

83.9

48.1

-35.4

<0.001

Study 4

Placebo 144 86.1 64.3 -22.2

Venlafaxine XR 133 86.2 51.5 -35.0 <0.001

Paroxetine

136

87.2

47.3

-39.2

<0.001

Long-term (6 month) Study

LSAS

Study 5

Placebo 126 89.3 65.6 -23.5

Venlafaxine XR (total)d 238 89.0 51.2 -37.8 <0.001

Venlafaxine XR 75mg 119 91.8 51.0 -38.1 <0.001

Venlafaxine 150-225mg

119

86.2

51.5

-37.6

<0.001

a: Flexible dose range for venlafaxine XR was 75-225mg/day; b: Data

shown are for ITT population; c: Flexible dose range for paroxetine

was 20-50mg/day; d: Primary treatment group. Abbreviations: ITT =

intent to treat; LSAS = Liebowitz Social Anxiety Scale

INDICATIONS

EFEXOR-XR is indicated for the treatment of:

Major depression

Generalised anxiety disorder;

Social Anxiety Disorder.

EFEXOR-XR is also indicated for the prevention of relapse and

recurrence of major depression where appropriate.

CONTRAINDICATIONS

Hypersensitivity to venlafaxine or any excipients in the formulation

Concomitant use of venlafaxine and any monoamine oxidase inhibitor-

(MAOI) is contraindicated. EFEXOR-XR must not be initiated for at

least 14 days after discontinuation of treatment with a MAOI. EFEXOR-

XR must be discontinued for at least 7 days before starting

treatment with any MAOI -(See PRECAUTIONS - Interactions with other

drugs).

PRECAUTIONS

Use in Patients with Renal Impairment

The total daily dose of venlafaxine must be reduced by 25% to 50%

for patients with renal impairment with a glomerular filtration rate

(GFR) of 10 to 70 mL/min.

The total daily dose of venlafaxine must be reduced by 50% in

haemodialysis patients. Administration must be withheld until the

dialysis session is completed.

Use in Patients with Hepatic Impairment

The total daily dose of venlafaxine must be reduced by 50% in

patients with moderate hepatic impairment. Reductions of more than

50% may be appropriate for some patients.

Sustained Hypertension

Dose-related increases in blood pressure have been reported in some

patients treated with venlafaxine.

Among patients treated with 75 to 375 mg per day of EFEXOR-XR in pre-

marketing depression studies, 3% (19/705) experienced sustained

hypertension [defined as treatment-emergent supine diastolic blood

pressure (SDBP) ( 90 mm Hg and ( 10 mm Hg above baseline for 3

consecutive on-therapy visits]. Among patients treated with 37.5 to

225 mg per day of EFEXOR-XR in pre-marketing GAD studies, 0.5%

(5/1011) experienced sustained hypertension. Experience with the

immediate-release venlafaxine showed that sustained hypertension was

dose-related, increasing from 3 to 7% at 100 to 300 mg per day to

13% at doses above 300 mg per day. An insufficient number of

patients received mean doses of EFEXOR-XR over 300 mg per day to

fully evaluate the incidence of sustained increases in blood

pressure at these higher doses.

In placebo-controlled pre-marketing depression studies with EFEXOR-

XR 75 to 225 mg per day, a final on-drug mean increase in supine

diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for EFEXOR-

XR treated patients compared with a mean decrease of 0.2 mm Hg for

placebo-treated patients. In placebo-controlled pre-marketing GAD

studies with EFEXOR-XR 37.5 to 225 mg per day up to 8 weeks or up to

6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was

observed for EFEXOR-XR treated patients compared with a mean

decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated

patients. In pre-marketing Social Anxiety Disorder studies up to 12

weeks, the final on-therapy mean change from baseline in SDBP was

small - an increase of 0.78 mmHg, compared to a decrease of 1.41

mmHg in placebo-treated patients. In a 6-month study, the final on-

therapy mean increase from baseline in SDBP with EFEXOR-XR 150 to

225 mg was 1.49 mmHg. The increase was significantly different from

the 0.6 mmHg decrease with placebo and the 0.2 mmHg decrease with

EFEXOR-XR 75 mg

In pre-marketing depression studies, 0.7% (5/705) of the EFEXOR-XR

treated patients discontinued treatment because of elevated blood

pressure. Among these patients, most of the blood pressure increases

were in a modest range (12 to 16 mm Hg, SDBP). In pre-marketing GAD

studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3%

(7/535) of the EFEXOR-XR treated patients, respectively,

discontinued treatment because of elevated blood pressure. Among

these patients, most of the blood pressure increases were in a

modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up

to 6 months).

Sustained increases of SDBP could have adverse consequences.

Therefore it is recommended that patients receiving EFEXOR-XR have

regular monitoring of blood pressure. For patients who experience a

sustained increase in blood pressure while receiving venlafaxine,

either dose reduction or discontinuation should be considered.

Increase in Serum Cholesterol

Clinically relevant increases in serum cholesterol were recorded in

5.3% of EFEXOR immediate release tablet-treated patients and 0.0% of

placebo-treated patients for at least 3 months in placebo-controlled

clinical trials.

Treatment with EFEXOR-XR for up to 12 weeks in pre-marketing placebo-

controlled depression trials was associated with a mean final on-

therapy increase in serum cholesterol concentration of approximately

0.039 mmol/L (1.5 mg/dL). EFEXOR-XR treatment for up to 8 weeks and

up to 6 months in pre-marketing placebo-controlled GAD trials was

associated with mean final on-therapy increases in serum cholesterol

concentration of approximately 0.026 mmol/L (1.0 mg/dL) and 0.059

mmol/L (2.3 mg/dL), respectively.

In the 12 week Social Anxiety Disorder studies, small mean increases

in fasting levels of total cholesterol (0.20 mmol/L, 4%) were seen

in the EFEXOR-XR-treated group at the final on-therapy evaluation;

the increases were significantly different from the changes in the

placebo group. In a 6-month study, the final on-therapy mean

increase in total cholesterol was higher (0.32mmol/L, 7%) in the

EFEXOR-XR 150 to 225 mg group; however the total cholesterol value

was slightly decreased (0.01mmol/L) for the EFEXOR-XR group.

There were also significant mean increases from baseline in LDL, but

not HDL for the EFEXOR-XR 150 to 225 mg group. The final on-therapy

increase of 0.213 mmol/L from baseline in LDL with EFEXOR-XR 150 to

225 mg was significantly different from the small decrease with

placebo (0.079 mmol/L) and the negligible increase with EFEXOR-XR

75mg (0.006 mmol/L).

Measurement of serum cholesterol levels should be considered during

long-term treatment.

Hyponatraemia

Cases of hyponatraemia, and/or the Syndrome of Inappropriate

Antidiuretic Hormone secretion (SIADH) may occur with venlafaxine,

usually in volume-depleted or dehydrated patients, including elderly

patients and in patients taking diuretics. These have resolved on

discontinuation of the drug.

Caution is advised in administering EFEXOR-XR to patients with

diseases or conditions that could affect haemodynamic responses or

metabolism.

Myocardial Infarction and Unstable Heart Disease

Venlafaxine has not been evaluated in patients with a recent history

of myocardial infarction or unstable heart disease. Therefore it

should be used with caution in these patients.

Patients with these diagnoses were systematically excluded from any

clinical studies during the product's trials.

Evaluation of the electrocardiograms for 769 patients who received

immediate release EFEXOR in 4 to 6-week double blind, placebo-

controlled trials showed that the incidence of trial-emergent

conduction abnormalities did not differ from that with placebo.

The electrocardiograms for patients who received EFEXOR-XR or

placebo in the depression GAD and Social Anxiety Disorder trials

were analysed. The mean change from baseline in corrected QT

interval (QTc) for EFEXOR-XR treated patients in depression studies

was increased relative to that for placebo-treated patients

(increase of 4.7 msec for EFEXOR-XR and decrease of 1.9 msec for

placebo). The mean change from baseline QTc for EFEXOR-XR treated

patients in the GAD studies did not differ significantly from

placebo. The final on-therapy mean increase from baseline in QTc (3

msec) was significant for Efexor-XR treated patients in the Social

Anxiety Disorder short-term studies. In the 6 month study, the final

on-therapy mean increase from baseline in QTc with EFEXOR-XR 150 to

225 mg (3 msec) was significant, but the increase was not

significantly different from the small mean increase (0.5 msec) with

placebo. The value for EFEXOR-XR 75mg was a 0.05 msec decrease.

Increases in heart rate may occur, particularly with higher doses.

Therefore caution is advised in patients whose underlying conditions

may be compromised by increases in heart rate.

The mean change from baseline in heart rate for EFEXOR-XR treated

patients in both the GAD and depression studies was significantly

higher than for placebo (a mean increase of 3-4 beats per minute for

EFEXOR-XR and 0-1 beat per minute for placebo in the GAD and

depression studies respectively). In the pooled short-term Social

Anxiety Disorder studies, the final on-therapy mean increase from

baseline in heart rate with EFEXOR-XR was 5 beats per minute. In the

6 month study, the final on-therapy mean increases from baseline in

heart rate were significant with EFEXOR-XR 75 (2 beats per minute)

and EFEXOR-XR 150 to 225 mg (6 beats per minute); however only the

increase with the higher dose was significantly different from the

small increase with placebo (0.4 beats per minute). The clinical

significance of these changes is unknown.

Mydriasis

Mydriasis may occur in association with venlafaxine. It is

recommended that patients with raised intra-ocular pressure or

patients at risk for acute narrow-angle glaucoma should be closely

monitored.

Abrupt Discontinuation of Efexor-XR

Discontinuation effects are well known to occur with

antidepressants. Discontinuation symptoms have been assessed both in

patients with depression and in those with anxiety. Abrupt

discontinuation, dose reduction, or tapering of venlafaxine at

various doses has been found to be associated with the appearance of

new symptoms, the frequency of which increased with increased dose

level and with longer duration of treatment.

Symptoms reported included agitation, anorexia, anxiety, confusion,

dry mouth, fatigue, paraesthesias, vertigo, hypomania, nausea,

vomiting, dizziness, convulsion, headache, diarrhoea, sleep

disturbance, insomnia, somnolence, sweating and nervousness. Where

such symptoms occurred, they were usually self-limiting, but in a

few patients lasted for several weeks.

There is also a report of a withdrawal syndrome, confirmed by two

challenges in a 32-year-old woman who had received venlafaxine 300

mg daily for 8 months. It is, therefore, recommended that the dosage

of EFEXOR-XR be tapered gradually and the patient monitored. The

period required for discontinuation may depend on the dose, duration

of therapy and the individual patient (See DOSAGE AND

ADMINISTRATION).

Altered Weight

Weight changes, either losses or gains, do not appear to present a

clinically important feature of venlafaxine treatment. Clinically

significant weight gain or loss was seen in less than 1% of patients

treated with venlafaxine during clinical trials. A dose-dependent

weight loss (mean loss <1 kg) was noted in some patients treated

with venlafaxine during the first few months of venlafaxine

treatment. After month 9, the mean weight began to increase slightly

but significantly, an effect often seen with tricyclic

antidepressant therapy. Significant weight loss (> 7 kg) was seen in

6 (0.3%) of 2,181 patients, compared to no patients treated with

placebo and 0.2% of patients treated with a comparative

antidepressant.

The safety and efficacy of venlafaxine therapy in combination with

weight loss agents, including phentermine, have not been

established. Co-administration of EFEXOR-XR and weight loss agents

is not recommended. EFEXOR-XR is not indicated for weight loss alone

or in combination with other products.

Suicide

The risk of suicide attempt must be considered in all depressed

patients. Prescriptions for EFEXOR-XR should be written for the

smallest quantity of capsules consistent with good patient

management in order to reduce the possibility of overdosage.

Seizures

Seizures may occur with venlafaxine therapy. EFEXOR-XR, as with all

antidepressants, should be introduced with care, in patients with a

history of seizure disorders. EFEXOR-XR should be discontinued in

any patient who develops seizures.

Activation of Mania/Hypomania

Mania/hypomania may occur in a small proportion of patients with

mood disorders treated with antidepressants, including venlafaxine.

Venlafaxine should be used cautiously in patients with a history of

mania.

Skin/Allergic Reactions

Patients should be advised to notify their physician if they develop

a rash, hives, or related allergic phenomena

Skin and Mucous Membrane Bleeding

The risk of skin and mucous membrane bleeding may be increased in

patients taking venlafaxine, particularly if predisposed to such

events. Venlafaxine should be used cautiously in patients

predisposed to bleeding at these sites.

Effects on Cognitive and Motor Performance

Although venlafaxine has been shown not to affect psychomotor,

cognitive or complex behaviour performance in healthy volunteers,

any psychoactive medication may impair judgment, thinking or motor

skills, and patients should be cautioned about operating hazardous

machinery, including automobiles, until they are reasonably certain

that the treatment does not affect them adversely.

Physical and Psychological Dependence

Clinical studies have shown no evidence of drug-seeking behaviour,

development of tolerance, or dose escalation over time among

patients taking venlafaxine. Consequently, physicians should

carefully evaluate patients for a history of drug abuse and follow

such patients closely observing them for signs of misuse or abuse of

venlafaxine (e.g. development of tolerance, increase in dose, drug-

seeking behaviour) (see PHARMACOLOGY).

Use in Elderly Patients

No overall differences in effectiveness or safety were observed

between elderly (aged 65 years and older) and younger patients.

EFEXOR-XR does not appear to pose any exceptional safety problems

for healthy elderly patients.

Effectiveness in elderly patients with social anxiety disorder has

not been established.

Paediatric Use

Safety and effectiveness in individuals below 18 years of age have

not been established. Efexor-XR should not be used in such patients.

As with adults, decreased appetite, weight loss, increased blood

pressure and increased serum cholesterol have been observed in

children and adolescents aged 6 to 17 years.

In paediatric clinical trials, there were increased reports of

hostility and, especially in major depressive disorder, suicide-

related adverse events such as suicidal ideation and self-harm.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Evidence of impairment of fertility was not noted in preclinical

toxicology studies.

Venlafaxine was given by oral gavage to mice and rats for 18 months

and 24 months respectively, at dosages up to 120 mg/kg/day. There

were no clear drug-related oncogenic effects in either species. In

these studies, animal exposure to the main human metabolite ODV was

less, and exposure to venlafaxine was more than would be expected in

humans taking the recommended therapeutic and maximum doses.

There was no evidence of gene mutation or chromosomal change in a

series of genotoxicity assays using venlafaxine and the main human

metabolite ODV.

Signs of pharmacologic toxicity were seen in paternal and maternal

rats given venlafaxine doses of 30 and 60 mg/kg/day, but no adverse

effect was noted in fertility or general reproductive performance.

Decreased foetal size and pup weight at birth with 60 mg/kg/day may

be correlated with maternal toxicity.

Use During Pregnancy

Category: B2

The safety of venlafaxine in human pregnancy has not been

established. There are no adequate and well-controlled studies in

pregnant women. Because animal reproductive studies are not always

predictive of human response, this medication should be used during

pregnancy only if clearly needed. Patients should be advised to

notify their physician if they become pregnant or intend to become

pregnant during therapy. If venlafaxine is used until or shortly

before birth, discontinuation effects in the newborn should be

considered.

In a rat teratology study, venlafaxine was given orally at dosages

up to 80 mg/kg/day (approximately 11 times the maximum recommended

human dose). Foetotoxicity evidenced by growth retardation was

slightly increased at 80 mg/kg/day, an effect which may be related

to maternal toxicity at this dose level. Foetal survival and

morphologic development were not affected. In another teratology

study, rabbits were given venlafaxine dosages up to 90 mg/kg/day.

Foetotoxicity evidenced by resorption and foetal loss was slightly

increased at 90 mg/kg/day; (approximately 12 times the maximum

recommended human dose). These effects could be correlated with

maternal toxicity. No venlafaxine-associated teratogenic effect was

noted in either species at any dosage, though there was an increased

incidence of 'W'-shaped apex of the heart in the rabbit study. In

these studies, animal exposure to the main human metabolite ODV was

less, and estimated exposure to venlafaxine was approximately 6-fold

more than would be expected in humans taking the recommended

therapeutic and maximum doses. In rats, estimated exposure to

venlafaxine was more than the expected human exposure. No

teratogenic effect was seen.

In a perinatal toxicity study in rats after oral dosing of dams with

30 mg/kg or more, decreased pup survival following birth was

observed. This effect is secondary to treatment-decreased maternal

care, and is also seen with other antidepressants.

Use During Lactation

Venlafaxine and/or its metabolites are secreted in milk of lactating

rats at concentrations higher than those found in the plasma of the

dam. Venlafaxine and its metabolites have been shown to pass into

human milk. The total dose of venlafaxine and O-desmethylvenlafaxine

ingested by breast fed infants can be as high as 9.2% of maternal

intake. Therefore, the use of EFEXOR-XR in nursing women cannot be

recommended. Exposed infants should be observed closely.

Interactions with other Drugs

Venlafaxine and ODV are 27% and 30% bound to plasma proteins

respectively, therefore interactions due to protein binding of

venlafaxine and the major metabolite are not expected.

Monoamine oxidase inhibitors

Concomitant use with EFEXOR is contraindicated.

Irreversible MAOI Inhibitors

Severe adverse reactions have been reported in patients who have

recently been discontinued from a MAOI and started on venlafaxine,

or have recently had venlafaxine therapy discontinued prior to

initiation of a MAOI or when these two agents are co-administered.

Reactions have included tremor, myoclonus, diaphoresis, nausea,

vomiting, flushing, dizziness, hyperthermia with features resembling

neuroleptic malignant syndrome and/or serotonergic syndrome,

seizures, and death. Do not use EFEXOR in combination with a MAOI or

within at least 14 days of discontinuing MAOI treatment. Allow at

least 7 days after stopping EFEXOR-XR before starting a MAOI (see

CONTRAINDICATIONS).

Reversible MAOI Inhibitors

EFEXOR should not be administered concomitantly with moclobemide.

There are no clinical trials to support the recommendation of a

specific time between discontinuing treatment with the reversible

MAOI, moclobemide and initiating EFEXOR therapy or switching to

moclobemide. Given the risk for adverse reactions described for

irreversible MAOIs (see above), an adequate washout period should be

ensured when switching a patient between EFEXOR and moclobemide. The

appropriate washout period should take into account the

pharmacological properties of venlafaxine and moclobemide and the

clinician's assessment of the individual patient. Based on the half-

lives of moclobemide, venlafaxine and ODV, the minimum washout

period should be 24 hours when switching from moclobemide to EFEXOR

and 7 days when switching from EFEXOR to moclobemide.

Warfarin

There have been reports of increases in prothrombin time, partial

thromboplastin time, or INR when venlafaxine was given to patients

receiving warfarin therapy.

Alcohol

Venlafaxine has not been shown to increase the impairment of mental

and motor skills caused by ethanol. However, as with all CNS active

drugs, patients should be advised to avoid alcohol consumption while

taking EFEXOR.

Cimetidine

Cimetidine inhibited the first-pass metabolism of venlafaxine but

had no apparent effect on the formation or elimination of ODV, which

is present in much greater quantity in the systemic circulation. No

dosage adjustment seems necessary when EFEXOR is co-administered

with cimetidine. However, for elderly patients or patients with

hepatic dysfunction, the interaction could potentially be more

pronounced and for such patients clinical monitoring is indicated

when EFEXOR is administered with cimetidine.

epam.

The pharmacokinetic profiles of venlafaxine and ODV were not altered

when venlafaxine and diazepam were administered together to healthy

volunteers. Venlafaxine had no effect on the pharmacokinetics of

diazepam or affect the psychomotor and psychometric effects induced

by diazepam.

Lithium

The steady-state pharmacokinetics of venlafaxine and ODV are not

affected when lithium is co-administered. Venlafaxine also has no

effect on the pharmacokinetics of lithium. (See also CNS Active

drugs.)

Haloperidol

Venlafaxine administered under steady-state conditions (75 mg twice

daily) to 24 healthy subjects decreased total oral 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 Cmax

increased 88% when co-administered with venlafaxine, but the

haloperidol elimination half-life (t½) was unchanged. The mechanism

explaining this finding is unknown.

Imipramine

Venlafaxine did not affect the CYP2D6-mediated 2-hydroxylation of

imipramine or its active metabolite, desimipramine, which indicates

that venlafaxine does not inhibit the CYP2D6 isoenzyme. However, the

renal clearance of 2-hydroxydesimipramine was reduced with co-

administration of venlafaxine.

Imipramine partially inhibited the CYP2D6-mediated formation of ODV,

however, the total concentrations of active compounds (venlafaxine

plus ODV) was not affected with imipramine administration.

Additionally, in a clinical study involving CYP2D6-poor and -

extensive metabolisers, the total sum of the two active species

(venlafaxine and ODV) was similar in the two metaboliser groups.

Therefore, no dosage adjustment is expected when venlafaxine is co-

administered with a CYP2D6 inhibitor. However, desipramine AUC,

Cmax, and Cmin increased by about 35% in the presence of

venlafaxine. There was an increase of 2-OH-desipramine AUC by 2.5 to

4.5 fold. The clinical significance of this finding is unknown.

Risperidone

Venlafaxine increased risperidone AUC by 32% but did not

significantly alter the pharmacokinetic profile of the total active

moiety (risperidone plus 9-hydroxy-risperidone). The clinical

significance of this interaction is unknown.

Indinavir

A pharmacokinetic study with indinavir has shown a 28% decrease in

AUC and a 36% decrease in Cmax for indinavir. Indinavir did not

affect the pharmacokinetics of venlafaxine and ODV. The clinical

significance of this interaction is unknown.

Antihypertensive and Hypoglycaemic Agents

Retrospective analysis of study events occurring in patients taking

venlafaxine concurrently with antihypertensive or hypoglycaemic

agents in clinical trials provided no evidence suggesting

incompatibility between treatment with venlafaxine and treatment

with either antihypertensive or hypoglycaemic agents.

CNS Active Drugs

Based on the known mechanism of action of venlafaxine and the

potential for serotonin syndrome, caution is advised when EFEXOR is

co-administered with other drugs that may affect the serotonergic

neurotransmitter systems (such as triptans, SSRIs or lithium).

No information is available on the use of EFEXOR in combination with

opiates.

There have been reports of elevated clozapine levels in association

with adverse events including seizures, following the administration

of venlafaxine.

As with other antidepressants, co-administration of EFEXOR and

products containing Hypericum perforatum (St. 's Wort) is not

recommended due to possible pharmacodynamic interactions.

Drugs that Inhibit Cytochrome P450 Isoenzymes

CYP2D6 Inhibitors

In vitro and in vivo studies indicate that venlafaxine is

metabolised predominantly to 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

(such as amiodarone and quinidine) and venlafaxine. Drug

interactions that reduce the metabolism of venlafaxine to ODV

potentially increase the plasma concentrations of venlafaxine and

lower the concentration of the active metabolite.

The concomitant use of venlafaxine with drug treatment(s) that

potentially inhibits both CYP2D6 and CYP3A4, the primary

metabolising enzymes for venlafaxine, has not been studied.

Therefore caution is advised if a patient's therapy includes

venlafaxine and any agent(s) that produces simultaneous inhibition

of these two enzyme systems.

CYP3A4 Inhibitors

In vitro studies indicate that venlafaxine is likely metabolised to

a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4.

Because CYP3A4 is a minor pathway relative to CYP2D6 in the

metabolism of venlafaxine, the potential for a clinically

significant drug interaction between inhibitors of CYP3A4-mediated

metabolism (such as erythromycin, fluconazole and grapefruit juice)

and venlafaxine is small.

Drugs Metabolised by Cytochrome P450 Isoenzymes

In vitro studies indicate that venlafaxine is a relatively weak

inhibitor of CYP2D6 and that venlafaxine does not inhibit CYP1A2,

CYP2C9 or CYP3A4. Some of these findings have been confirmed with

drug interaction studies between venlafaxine and imipramine

(metabolised by CYP2D6) and diazepam (metabolised by CYP2C19).

Therefore, EFEXOR-XR is not expected to interact with other drugs

metabolised by these isoenzymes.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of EFEXOR-XR

combined with electroconvulsive therapy.

Effects on Laboratory tests

No interference on laboratory tests by venlafaxine is known.

ADVERSE REACTIONS

Adverse reactions are listed in the following table in CIOMS

frequency categories:

Common: = 1%; Uncommon: = 0.1% and <1%; Rare: = 0.01% and <0.1%;

Very rare: <0.01%.

Body System

Adverse Reactions

Body As A Whole

Common:

Asthenia/fatigue.

Uncommon:

Photosensitivity reaction.

Very rare:

Anaphylaxis.

Cardiovascular

Common:

Hypertension, vasodilatation (mostly hot flashes/flushes).

Uncommon:

Hypotension, postural hypotension, syncope, tachycardia.

Very rare:

QT prolongation, ventricular fibrillation, ventricular tachycardia

(including torsade de pointes).

Digestive

Common:

Appetite decreased, constipation, nausea, vomiting.

Uncommon:

Bruxism.

Undetermined Frequency:

Pancreatitis.

Haematological/Lymphatic

Uncommon:

Ecchymosis, mucous membrane bleeding.

Rare:

Prolonged bleeding time, thrombocytopenia.

Undetermined Frequency:

Blood dyscrasias (including agranulocytosis, aplastic anemia,

neutropenia and pancytopenia)

Metabolic/Nutritional

Common:

Serum cholesterol increased (particularly with prolonged

administration and with higher doses), weight loss.

Uncommon:

Abnormal liver function tests, hyponatraemia, weight gain.

Rare:

Hepatitis, syndrome of inappropriate antidiuretic hormone secretion

(SIADH).

Undetermined Frequency:

Prolactin increased.

Musculoskeletal

Undetermined Frequency:

Rhabdomyolysis.

Nervous

Common:

Abnormal dreams, decreased libido, dizziness, dry mouth, increased

muscle tonus, insomnia, nervousness, paraesthesia, sedation, tremor.

Uncommon:

Apathy, hallucinations, myoclonus.

Rare:

Convulsion, manic reaction, neuroleptic malignant syndrome (NMS),

serotonergic syndrome.

Undetermined Frequency:

Agitation, delirium, extrapyramidal reactions (including dystonia,

and dyskinesia), tardive dyskinesia.

Respiratory

Common:

Yawning.

Undetermined Frequency:

Pulmonary eosinophilia.

Skin

Common:

Sweating (including Night Sweats).

Uncommon:

Rash, alopecia.

Very Rare:

Erythema multiforme, s- syndrome.

Special Senses

Common:

Abnormality of accommodation, mydriasis, visual disturbance.

Uncommon:

Altered taste sensation.

Undetermined Frequency:

Tinnitus.

Urogenital

Common:

Abnormal ejaculation/orgasm (males), anorgasmia, erectile

dysfunction, urination impaired (mostly hesitancy)

Uncommon:

Abnormal orgasm (females), menorrhagia, urinary retention,

proteinuria.

Discontinuation effects are well known to occur with

antidepressants, and it is therefore recommended that the dosage is

tapered gradually and the patient monitored (see DOSAGE AND

ADMINISTRATION). The following symptoms have been reported in

association with abrupt discontinuation or dose-reduction, or

tapering of treatment: hypomania, anxiety, agitation, nervousness,

confusion, insomnia or other sleep disturbances, fatigue,

somnolence, paraesthesia, dizziness, convulsion, vertigo, headache,

sweating, dry mouth, anorexia, diarrhoea, nausea, and vomiting. The

majority of discontinuation reactions are mild and resolve without

treatment.

In the Social Anxiety Disorder pooled short-term studies, the most

common taper/post-study-emergent adverse events were dizziness

(13%), nausea (7%), insomnia (3%), nervousness (3%) and asthenia

(2%). In the 6-month study, the most common taper/post-study

treatment emergent adverse events were dizziness (21% and 16%) and

nausea (7% and 10%) for EFEXOR-XR 75 mg and EFEXOR-XR 150-225 mg,

respectively.

Paediatric Patients (see PRECAUTIONS - Paediatric Use)

In general, the adverse reaction profile of venlafaxine in placebo-

controlled clinical trials in children and adolescents (aged 6 to

17) was similar to that seen for adults.

As with adults, decreased appetite, weight loss, increased blood

pressure and increased serum cholesterol were observed.

Additionally, the following adverse reactions were observed:

abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis and

myalgia.

In paediatric clinical trials, there were increased reports of

hostility and, especially in major depression, suicide-related

adverse events such as suicidal ideation and self-harm.

DOSAGE AND ADMINISTRATION

Usual Dose

The usual recommended dose for the treatment of major depression,

generalised anxiety disorder or social anxiety disorder is 75 mg per

day given once daily. After two weeks, the dose may be increased to

150 mg per day given once daily if further clinical improvement is

required. If needed, this can be increased up to 375 mg given once

daily. Dose increments should be made at intervals of approximately

2 weeks or more, but not less than 4 days.

Antidepressant activity with the 75 mg dose was observed after 2

weeks of treatment and anxiolytic activity was observed after one

week.

It is recommended that EFEXOR-XR be taken with food. Each capsule

should be swallowed whole with fluid. Do not divide, crush, chew or

place the capsule in water. EFEXOR-XR should be administered once

daily, at approximately the same time either in the morning or in

the evening.

Depressed patients who are currently being treated at a therapeutic

dose with immediate-release venlafaxine may be switched to EFEXOR-XR

or vice versa at the nearest equivalent dose (mg/day). However,

individual dosage adjustments may be necessary.

Patients with Renal or Hepatic Impairment

Patients with renal and/or hepatic impairment should receive lower

doses of EFEXOR-XR. It may be necessary to initiate treatment in

these patients with immediate-release venlafaxine tablets. Patients

whose glomerular filtration rate (GFR) is less than 30 mL/min should

have their dosage reduced by 50%. Haemodialysis clearances of both

venlafaxine and ODV in humans are low. Nonetheless, it is

recommended that the daily dose of EFEXOR-XR be withheld from

patients who require dialysis treatment until after completion of

the dialysis treatment. Patients with moderate hepatic impairment

should also have their dosage reduced by 50%. Further reductions in

dosage should be considered for patients with more severe degrees of

hepatic impairment.

Elderly Patients

No adjustment in the usual dose is recommended for elderly patients

solely because of their age. As with any antidepressant, however,

caution should be exercised in treating the elderly. When

individualising the dosage, extra care should be taken when

increasing the dose.

Maintenance/Continuation/Extended Treatment

The physician should periodically re-evaluate the usefulness of long-

term EFEXOR-XR treatment for the individual patient. It is generally

agreed that acute episodes of major depression require several

months or longer of sustained pharmacological therapy. Whether the

dose of antidepressant needed to induce remission is identical to

the dose needed to maintain and/or sustain euthymia is unknown.

Usually, the dosage for prevention of relapse or for prevention of

recurrence of a new episode is similar to that used during initial

treatment. Patients should be regularly re-assessed in order to

evaluate the benefit of long-term therapy.

In Social Anxiety Disorder, continuing therapeutic benefit has been

established for periods of up to 6 months. The need for continuing

medication in patients with Social Anxiety Disorder who improve with

EFEXOR-XR treatment should be periodically assessed.

Discontinuing EFEXOR-XR

When EFEXOR-XR at a dose of 75 mg/day or greater has been

administered for more than 1 week is stopped, it is generally

recommended that the dose be tapered gradually to minimise the risk

of discontinuation symptoms. Patients who have received EFEXOR-XR

for 6 weeks or more should have their dose tapered gradually over at

least a 2-week period. To facilitate tapering below 75 mg of Efexor-

XR, physicians may consider switching some patients from 75 mg of

Efexor-XR once daily to 37.5 mg venlafaxine immediate-release

tablets twice daily, and then to 37.5 mg venlafaxine immediate-

release tablets once daily (see also Usual Dosage above). The period

required for tapering may depend on the dose, duration of therapy,

and the individual patient. Patients should be advised to consult

their physician before abruptly discontinuing EFEXOR-XR.

OVERDOSAGE

In managing overdosage, consider the possibility of multiple

medication involvement. The physician should consider contacting a

poison control centre on the treatment of any overdose. (See

PRECAUTIONS - Interactions with other drugs).

During pre-marketing trials, most patients who have overdosed with

venlafaxine were asymptomatic. Of the remainder, somnolence was the

most commonly reported symptom. Mild sinus tachycardia and mydriasis

have also been reported. There were no reports of seizures,

respiratory distress, significant cardiac disturbances, or

significant laboratory test result abnormalities among any of the

cases reported to date. However, seizures and respiratory distress

occurred in one patient in an on-going study who ingested an

estimated 2.75g of venlafaxine with naproxen and thyroxine.

Generalised convulsions and coma resulted and emergency

resuscitation was required. Recovery was good without sequelae.

In post-marketing experience, electrocardiogram changes (e.g.

prolongation of QT interval, bundle branch block, QRS prolongation),

sinus and ventricular tachycardia, bradycardia, hypotension,

vertigo, change in level of consciousness (ranging from somnolence

to coma), and seizures have been reported in association with

overdosage of venlafaxine, either alone or in combination with other

drugs and/or alcohol. Such events are rare and usually resolved

spontaneously. Also from post-marketing experience, there have been

reports of fatalities in patients taking overdoses of venlafaxine,

predominantly in combination with alcohol and/or other drugs.

Management of Overdosage

General supportive and symptomatic measures are recommended. Ensure

an adequate airway, oxygenation and ventilation. Cardiac rhythm and

vital signs must be monitored. Administration of activated charcoal

may also limit drug absorption. Where there is a risk of aspiration,

induction of emesis is not recommended. No specific antidotes for

venlafaxine are known. Forced diuresis, dialysis, haemoperfusion and

exchange transfusion are unlikely to be of benefit. Venlafaxine and

ODV are not considered dialyzable because haemodialysis clearance of

both compounds is low.

PRESENTATION

EFEXOR-XR is available for oral use as opaque peach (75 mg) or

opaque dark orange (150 mg) modified release capsules with a 'W' and

strength printed in red or white, respectively.

EFEXOR-XR is packed in blister packs in pack sizes of 7 and 28.

MEDICINE CLASSIFICATION

PRESCRIPTION ONLY MEDICINE

STORAGE

Store below 30°C.

NAME AND ADDRESS

Wyeth (NZ) Limited

15B Vestey Drive,

Mt Wellington,

AUCKLAND

Phone: (09) 573 5100

®Registered Trade mark

Date of preparation:

9 December 2003

> Hi, I'm new. I haven't read much of the board yet, but I thought

I

> would post the link to the ACNP Task Force " PRELIMINARY REPORT OF

THE

> TASK FORCE ON SSRIs AND SUICIDAL BEHAVIOR IN YOUTH "

>

> http://www.acnp.org/exec_summary.pdf

>

> Please note that members of the task force are also the

researchers

> who did some of the original studies that were reviewed. Also

check

> the drug company connections of the task force members listed in

the

> final pages.

>

> I would also like to point out the the single most effective and

> safest treatment for depression has consistently been proven by

the

> drug companies clinical double blind studies to be the placebo.

In

> most (all?) cases, the studied medication out perform the placebo

by

> less than 20%, often in the 5-10% range while the improvement rate

for

> the placebo was consistently above 35%, in at least one case as

high

> as 60%. The more the researchers refine the definition of

improvement

> in depressive symptoms so that the drug scores higher, the placebo

> also scores higher.

January 25, 2004