Venlafaxine (Effexor^®)

Original Author: Vicki Ellingrod, Pharm.D., BCPP
Latest Reviser: Vicki Ellingrod, Pharm.D., BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed

Currently 8 TCAs are available in this country. In 1979 trazodone (Desyrel) was the first second-generation antidepressant marketed in the U.S. There are now 6 additional agents in this class. Fluoxetine (Prozac) was the first of the selective serotonin reuptake inhibitors (SSRIs) to be marketed and it has been available since February 1988. Since that time 2 additional SSRIs have been marketed, sertraline (Zoloft) and paroxetine (Paxil). It is expected that fluvoxamine, another member of this class will be available within the year. A general review of two new antidepressants venlafaxine (Effexor) and nefazodone (Serzone) will be presented here.

MECHANISM OF ACTION

That depression is the result of dysregulation of serotonin and norepinephrine neurotransmitters has been theorized for many years. It is generally concluded that dysregulation leads to a relative functional deficiency of these neurotransmitters. Venlafaxine's primary mechanism is to increase the amount of serotonin and norepinephrine in the synaptic cleft by inhibiting their reuptake. Nefazodone's mechanism is to increase the amount of serotonin by inhibition of reuptake and antagonism at 5HT₂ receptors. Nefazodone also has the ability to inhibit norepinephrine reuptake.

EFFICACY

Typically studies with these drugs involve outpatients, are double-blind, and are 6 weeks in duration. Overall, approximately 65% of patients will be improved with these drugs. Few studies have examined the prophylactic effect of these drugs in recurrent major depressive disorder. Many of the clinical trials for these drugs are not published and thus the majority of efficacy data is obtained from FDA reports. Due to the lack of published reports, statistical analysis of these trials is very sparse.

Venlafaxine. In 8 controlled trials, venlafaxine was more effective than placebo in 6 studies and equal in efficacy in 2. In comparison studies to TCAs (e.g., imipramine and trazodone), venlafaxine was more effective than the reference TCA in 1, and equal in efficacy in 1.

In a 6 week study directly comparing venlafaxine and fluoxetine in patients with MDD with melancholia, both venlafaxine was found to be more effective than fluoxetine at week 4 and 6 (p< 0.05)

A complete list of controlled and uncontrolled studies is in table 2.

PHARMACOKINETICS

These drugs are extensively metabolized by the liver to weakly active or pharmacologically active metabolites. Liver disease may increase blood levels of the drugs, while renal impairment would not be expected to alter the drugs' elimination.

Absorption and Distribution. Venlafaxine hydrochloride is rapidly absorbed after oral administration and metabolized extensively in the liver. Food has no effect on the absorption of this drug, or on the formation of ODV. Venlafaxine's half life is 4 hours. Its primary metabolite, O-desmethylvenlafaxine (ODV) has a half life of 10 hours. This drug has the advantage over fluoxetine, which has a half-life of 3 to 7 days in that they leave the body quickly after discontinuation. That means they only need to be discontinued one week before initiating a monoamine oxidase inhibitor. This compares to a 5 week wait after fluoxetine discontinuation. The time to reach maximum plasma concentration (t_max) for venlafaxine was 2.0 hours with a mean absorption time (t_abs) of 1.5 hours. The t_max for ODV was between 2.3-3.0 hours and the t_abs was 2.2 hours. The mean volume of distribution of venlafaxine for all doses was 6 L/kg, with the volume of distribution for ODV 5 L/kg. As suggested by the drug's pKa of 9.4, venlafaxine and ODV are bound to albumins, a-amino glycoproteins, and lipoproteins. However, only 30% of the drug is protein bound. This low level of protein binding, independent of drug concentration, suggests that drug interactions associated with protein binding are not expected with venlafaxine.

Metabolism and Excretion. Venlafaxine is extensively metabolized in the liver by cytochrome P₄₅₀IID6. It's metabolism is a saturable process that produces two less active metabolites (N-desmethyl and N,O,-didesmethyl metabolite) and one active metabolite (O-desmethylvenlafaxine). ODV is 0.2 to 0.33 times as active of a reuptake inhibitor as the parent compound. Venlafaxine display non-linear kinetics with continuous administration. The breakpoint for non-linear kinetics is about 225 mg/day. Clinically, drugs that display linear kinetics will have a linear increase in blood levels with a dosage increase (i.e. double the dose, double the blood level) while a drug that exhibits non-linear kinetics will have an exponentially higher increase in blood levels after a dosage increase. This non-linearity may cause increased side effects due to high blood levels or may become important when this drug is administered with other medications whose metabolism it inhibits. Venlafaxine and its metabolites are primarily renally cleared. Therefore a dosage adjustment in patients with renal or hepatic dysfunction is needed.

Venlafaxine needs to be dosed twice daily due to their short half lives. In patients with sever hepatic or renal impairment, venlafaxine may be dose once daily.

ADVERSE EFFECTS

Patients generally tolerate these drugs better than TCAs as more patients drop out of treatment that are receiving TCAs.

Common side effects for venlafaxine include autonomic (i.e., dizziness, dry mouth, insomnia, and nervousness), CNS (i.e., asthenia, headache, and somnolence), gastrointestinal (i.e., nausea, constipation, and anorexia), and sexual dysfunction (i.e., abnormal ejaculation or abnormal orgasm) See Table 1.

Table 1. Treatment-Emergent Study Events ("10%) for venlafaxine versus comparator antidepressants and placebo
Organ Study Event	Placebo (n=451)	Venlafaxine (n=1902)	Imipramine (n=240)	Trazodone (n=77)
Autonomic Nervous System Dizziness	30 (7%)	418 (22%)	60 (25%)	29 (38%)
Dry Mouth	50 (11%)	387 (20%)	136 (57%)	20 (26%)
Insomnia	45 (10%)	458 (24%)	43 (18%)	5 (6%)
Nervousness	25 (6%)	295 (16%)	33 (14%)	8 (10%)
Central Nervous System Asthenia	31 (7%)	302 (16%)	44 (18%)	12 (16%)
Headache	111 (25%)	602 (32%)	68 (28%)	23 (30%)
Somnolence	44 (10%)	468 (25%)	79 (33%)	49 (64%)
Gastrointestinal Anorexia	8 (2%)	198 (10%)	20 (8%)	1 (1%)
Constipation	26 (6%)	312 (16%)	59 (25%)	8 (10%)
Nausea	49 (11%)	749 (39%)	45 (19%)	18 (23%)
Urogenital System (Male) Abnormal ejaculation/ Abnormal orgasm	(n=170) 0 (0%)	(n=737) 81 (11%)	(n=95) 4 (4%)	(n=24) 3 (13%)

DOSAGE

The recommended venlafaxine dosage range is 75-200 mg/day administered twice daily with or without food. Starting doses are usually within the range of 75-150 mg/day. This dosage may then be increased by 75 mg every 4 days, but may need to be done slower due to an increased incidence of side effects within the first 1-2 weeks of treatment. The maximum recommended dose is 375 mg/day. The dosage reduction for patients with renal dysfunction 25-100 mg/day in patients with GFR < 30 ml/min. In patients with hepatic dysfunction the dosage should be approximately 25-100 mg/day for patients with a PT between 14-18 seconds and for those with PTs > 18 the dose should be 1/6th of the normal dose. No dose reduction is needed in the elderly if no hepatic or renal dysfunction exists.

PRECAUTIONS/CONTRAINDICATIONS

Venlafaxine has been shown to interact with MAOIs (phenelzine). A period of at least 7 days is needed after the drug is discontinued before a MAOI can be administered.. Likewise, Venlafaxine should not be started within 14 days of discontinuation of a MAOI.

Venlafaxine supine diastolic blood pressure with doses > 300 mg/day. The prevalence of this increased blood pressure is 3% for venlafaxine, 2% for imipramine, 1% for placebo, and 0% for trazodone.

Abrupt discontinuation of venlafaxine is not recommended due to its structural similarity to phencyclidine (PCP). If therapy with venlafaxine is > 1 week the dose should be tapered over 7-10 day to prevent a withdrawal syndrome (headache, nausea, dizziness, insomnia and nervousness).

DRUG INTERACTIONS

Venlafaxine is metabolized by CYP2D6 and has saturable metabolism after 225 mg/day. This saturation may 'tie' up the enzyme and contribute to decreased metabolism of other drugs also metabolized by this route. Other drugs that inhibit CYP2D6 such as paroxetine or fluoxetine will increase venlafaxine serum concentrations. Cimetidine has been found to increase venlafaxine concentrations by 60%.

COST COMPARISONS

Average wholesale price (AWP) for a month's supply of drug provides a relative cost comparison.

A month's supply of venlafaxine at 75 mg BID is $59.69.

In comparison, the cost for sertraline 50 and 100 mg/d is $47.00 and $49.00. Fluoxetine for 10 mg, 20 mg, and liquid is $59.00, $58.00, and $107.00 (20 mg/d), respectively. Paroxetine for the 20 mg and 30 mg doses is $52.00 and $53.00, respectively.

Depending on the dose prescribed, these agents are approximately equivalent price. Splitting tablets of sertraline 100 mg or dosing fluoxetine 20 mg QOD can reduce the cost by approximately 50%.

CONCLUSIONS/RECOMMENDATIONS

1. All antidepressants are equally effective in treating depression.
2. Studies in TCA-refractory patients need to be performed. Only venlafaxine has been shown to be effective in refractory patients in an open study.
3. Venlafaxine may not be drugs of choice in patients with cardiovascular problems. If no other alternatives exist use venlafaxine cautiously and monitor frequently.
4. More studies need to be conducted to look at the side effect profile for these medications.
5. Dosage titration of newer agents may need to be done slowly so as to avoid potential side effects.
6. Venlafaxine is an expensive antidepressant compared to generically prescribed TCAs.
7. Venlafaxine's role in the therapy for the treatment of depression need to be defined.

Table 2. Summary of Trials of Venlafaxine Hydrochloride in Patients with Depression
Protocol Number	Study Design	No. Patients	druga mean dose (mg/d x wks)	Psychiatric Rating Scalesb	Results
600A-201	phase 2 open, uncontrolled	15	VLF, 251-300 x 4	HAMD, MADS, CGI	VLF = PLB. At 4 weeks, 62% of patients responsive (HAMD)
600A-202	phase 2 open, uncontrolled	80	VLF, 300 x 6	HAMD, MADS, CGI	60-75% of patients responded to treatment (HAMD, MADS). CGI mod to marked improvement
600A-204	phase 2 open, uncontrolled continuation of 600A-203	5	VLF, 75-375 x 12 wks-1 yr	HAMD, MADS, CGI	4 patients maintained response up to 1 yr.
600A-205	phase 2 open, uncontrolled	33	VLF, 97-100 x 6	HAMD, MADS, CGI	VLF > PLB week 4 and 6
600A-207	phase 2 open, uncontrolled	10	VLF 25 x 1 day, then 50 x 2 days, then 75 x 4 days, then 50 x 2 days	HAMD, MADS, CGI	HAMD, MADS, and CGI all non-significantly decreased by day 8
600A-206	phase 3 randomized, double-blind, placebo controlled	93	VLF, 350 x 4	HAMD, MADS, CGI-S	VLF >PLB (MADS day 4, HAMD day 7 and CGI-S day 14)
600A-203	phase 3 randomized, placebo controlled, fixed dose	323	VLF, 71-356 x 6	HAMD, MADS, CGI-S	VLF (all doses) > PLB (HAMD 2 wk, MADS 3 wk, and CGI-S 4 wk). Lower dose (75 mg/d), least effective.
600A-313	phase 3 randomized, placebo controlled, fixed dose	312	VLF, 24-191 x 6	HAMD, MADS, CGI	VLF (all doses) > PLB (MADS and CGI-S by wk 3 and HAMD by wk 4)
600A-301	phase 3 randomized, double-blind, placebo controlled	213	VLF, 168-182 x 6 IMP, 157-176 x 6	HAMD, MADS, CGI-S	VLF > PLB, IMP> PLB, VEN = IMP at week 6
600A-302	phase 3 double-blind, placebo controlled	225	VLF, 75-200 x 6 TRZ, 150-400 x 6	HAMD, MADS, CGI	VLF> PLB, TRZ>PLB (HAMD at 4 wk and MADS at 6 wk) 55% PLB, 72% VLF and 60% TRZ were much or very, much improved on CGI.
600A-303	phase 3 randomized, placebo controlled	221	VLF, 185-189 x 6 IMP, 177-185 x 6	HAMD, HAMD-D, MADS, CGI-S	VLF = PLB, IMP = PLB
600A-340-BE, FR	phase 3 randomized, placebo controlled, parallel group	68	VLF, 150-200 x 6 FLX, 20-40 x 6	HAMD, MADS, CGI-S, HAD	70% of VLF, and 50% FLX patients showed " 50% decrease in MADS score
600A-310	phase 3 open-label	381	VLF, 154-176 x 1 yr IMP, 138-160 x 1 yr	CGI	VLF = IMP
600A-328-US	phase 3 open-label	84	VLF, 245±99 x 24	HAMD, MADS, CGI-S+I	At wk 8, 33% showed mean HAMD dec. by 42% and mean MADS dec. by 39%. Effect was sustained at wk 24 by 46% of initial responders

1. Dosages are expressed in mg/day. VLF = venlafaxine hydrochloride, IMP = imipramine hydrochloride, TRZ = trazodone hydrochloride, FLX = fluoxetine hydrochloride, and PLB = placebo
2. HAMD = Hamilton Rating Scale for Depression, HAMD-D= Hamilton Rating Scale for Depression-Depressed Mood Item, CGI = Clinical Global Impression, CGI-S= Clinical Global Impression-Severity, CGI-S+I = Clinical Global Improvement-Severity and Improvement, and MADS = Montgomery-Asberg Depression Rating Scale.

REFERENCES

Ellingrod VL and Perry PJ (1994). Venlafaxine: a heterocyclic antidepressant. Am J Hosp Pharmacy; 51: 3033-3046.

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