This first page is the Official Q&A about  venlafaxine.  The second post is a list of Patients Q&A which I compiled from trawling through posts asked by members of DF.  

Hope they are both of use.  

firelizardee.


EFFEXOR XR ®
VENLAFAXINE HCl

Questions and Answers about XR

INTRODUCTION

EFFEXOR® XR (venlafaxine HCI) adds the convenience of once-daily dosing to the well-established antidepressant efficacy of immediate-release EFFEXOR® XR (venlafaxine HCI.1 Once-daily dosing may make EFFEXOR XR more acceptable to many patients who might benefit from it, including those with associated symptoms of anxiety, and those taking multiple medications who might be at risk of drug interactions.

What is the mechanism of action of EFFEXOR XR?

EFFEXOR XR is a potent inhibitor of the reuptake of serotonin and norepinephrine2- two neurotransmitters thought to play important roles in the pathophysiology of depression.3,4 However, it has virtually no affinity for other receptors which are hypothesized to be associated with the anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs, including the tricyclic antidepressants.2,5 As with SSRIs, anticholinergic-like side effects may occur with EFFEXOR XR.

What are the benefits of combining reuptake inhibition of serotonin and norepinephrine?

Research suggests that changes in the serotonergic and noradrenergic systems have different effects on behavior and emotion. Serotonin (5HT) has been associated with the mood aspects of the depression, especially anxiety and depressed mood, while norepinephrine has been primarily associated with the psychomotor components, and only secondarily with mood.6 Thus, an antidepressant with a combined mode of action should be able to affect the actions of both neurotransmitters.

How does EFFEXOR XR differ from EFFEXOR?

EFFEXOR XR provides all the efficacy of immediate-release venlafaxine, with the additional benefit of once-daily convenience, especially for patients on the go and those with complicated medication schedules.

In premarketing studies of EFFEXOR, the rate of discontinuation of treatment due to adverse events was 19%. In premarketing studies of EFFEXOR XR, the rate of discontinuation of treatment due to adverse events was approximately 11%.

What is the pharmacokinetic profile of EFFEXOR XR?

EFFEXOR XR attains steady-state plasma concentrations of venlafaxine and its major active metabolite, O-desmethylvenlafaxine (ODV), within 3 days of oral multiple-dose administration. Venlafaxine and ODV exhibited linear kinetics over the dosage range of 75 to 450 mg/day.

In equal daily doses, once-daily EFFEXOR XR capsules and BID immediate-release EFFEXOR tablets have similar bioavailability as measured by areas under the curve (AUC) for both venlafaxine and ODV.2 For venlafaxine and ODV, the approximate times to peak plasma concentration are 6.0 and 8.8 hours, respectively. The degrees of plasma protein binding are approximately 27% and 30%, respectively, at plasma concentrations ranging from 100 to 500 ng/mL. EFFEXOR XR had the same extent of absorption, but at a slower rate than immediate-release EFFEXOR.2

Excretion. For venlafaxine and ODV, the approximate elimination half-lives are 5 and 11 hours, respectively. Venlafaxine and its metabolics are excreted primarily via the kidneys. After a single radiolabeled venlafaxine dose, 87% was recovered in the urine within 48 hours, mostly as conjugated and unconjugated ODV and other metabolites. The elimination half-life did not change between EFFEXOR and EFFEXOR XR.

Special populations. Venlafaxine and ODV pharmacokinetics appear to be unaffected by age, gender, or administration with or without food.

Is there a cost difference between EFFEXOR and EFFEXOR XR?

All three strengths of EFFEXOR XR (37.5 mg, 75mg, and 150 mg) are priced comparably to equal daily doses of immediate-release EFFEXOR.



DOSING

What are the dosage strengths of EFFEXOR XR?

EFFEXOR XR is available in three dosage strengths: 37.5 mg, 75 mg, and 150 mg, each designed for once-daily administration.



For most patients, the recommended starting dose of EFFEXOR XR is 75 mg/day, administered in a single dose.

For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow patients to adjust to the medication before increasing to 75 mg/day. The 37.5-mg capsule may be used in these patients or in patients with moderate hepatic or renal impairment. Some patients may require individualized dosage.2

The 75-mg capsule, the usual starting dose, has demonstrated high response rates in clinical trials.2*

The 150-mg capsule may offer a benefit for patients who have not responded adequately to 75 mg/day.1,2
How should patients take EFFEXOR XR?

EFFEXOR XR should be taken in a single daily dose with food, either in the morning or in the evening, at approximately the same time each day.2 Instruct patients to take each capsule whole, with fluid, and not divide, crush, chew, or place in liquid prior to administration.

How can I dose EFFEXOR XR for optimum results in specific patients?

Patients with more severe depression. Patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady-state plasma levels of venlafaxine and its metabolite are achieved in most patients by 4 days.

*When increasing the dosage, increments of up to 75 mg/day should be made at intervals of no less than 4 days.

It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for EFFEXOR (the immediate-release form of venlafaxine), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of EFFEXOR XR are needed for more severely depressed patients is unknown; however, the experience with EFFEXOR XR doses higher than 225 mg/day is very limited.

Are dosage adjustments needed for the elderly, or renally or hepatically impaired patients?

Elderly: No dosage adjustment is necessary based on age alone. As with any antidepressant, however, caution should be exercised in treating the elderly.

Renally impaired: Reduced total daily dose by 25% in-patients with mild-to-moderate impairment; 50% for dialysis patients (administer dose 4 hours after completion of dialysis).

Hepatically impaired: Reduce dose by 50% in moderately impaired patients: a further reduction may be required in some patients with cirrhosis.

How do I switch patients to EFFEXOR XR?

From EFFEXOR to EFFEXOR XR? Patients being treated with EFFEXOR may be switched to EFFEXOR XR at the nearest equivalent (mg/day) dose. For example, 75 mg of EFFEXOR is equivalent to 75 mg of EFFEXOR XR, so EFFEXOR XR 75 mg once daily would replace EFFEXOR 37.5 mg BID. Individual dosage adjustments may be necessary.

When discontinuing EFFEXOR XR after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Patients discontinuing EFFEXOR XR after 6 weeks or more should have their dose tapered gradually over a 2-week period. Individualization of tapering may be necessary.

From other antidepressants: general considerations. There are no clinical trials to definitively answer questions about switching. Factors to bear in mind when evaluating the initial response to EFFEXOR XR include the half-life of the previous drug, the possibility of addictive effects and drug-drug interactions, and the potential for tricyclic or SSRI discontinuation symptoms.

In certain patients, clinical considerations should be given to:


Those who have received high doses of the previous drug

Those who have experienced adverse affects of the previous drug
From an SSRI to EFFEXOR XR? The half-lives of antidepressants should be considered when switching from SSRIs to EFFEXOR XR. Keep in mind that SSRIs with longer half-lives have longer elimination periods during which the two drugs may interact pharmacokinetically or have additive serotonergic effects.2,7,8

From a TCA to EFFEXOR XR? Since discontinuation symptoms may occur if the TCA is abruptly withdrawn,9 clinicians should evaluate the washout period needed for the TCA before initiating EFFEXOR XR.

From an MAOI to EFFEXOR XR? EFFEXOR XR should not be used within at least 14 days of discontinuing treatment with an MAOI because of the potential for serious adverse reactions. Based on the half-life of EFFEXOR XR, at least 7 days should be allowed after stopping EFFEXOR XR before starting an MAOI.

How can I increase/augment the benefits of EFFEXOR XR?

Increasing doses of immediate-release venlafaxine may result in a progressively higher incidence of response. Data from two fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. While the relationship between dose and antidepressant response for EFFEXOR XR has not been adequately explored, patients not responding to the initial 75-mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. This positive dose response may reduce the need to switch agents, augment the regimen, or refer patients.1,2

Partial responders. Although the 75-mg capsule is the usual starting dose, some patients may benefit from increased doses up to 225 mg/day.1,2 When increasing the dosage, increments of up to 75 mg/day should be made at intervals of no less than 4 days.



PATIENTS

Are there depressed patients for whom EFFEXOR XR is especially suitable?

Venlafaxine has demonstrated efficacy in a wide variety of patients:


Outpatients who had major depression even with associated anxiety symptoms2

Elderly depressed patients and patients at risk for drug interactions
Can EFFEXOR XR be used safely in patients who consume alcohol?

EFFEXOR XR has not been shown to increase the alcohol-induced impairment of mental and motor skills. Nevertheless, advise patients taking EFFEXOR XR to avoid alcohol.

Are there patients for whom EFFEXOR XR is not recommended?

EFFEXOR XR is contraindicated in patients known to be hypersensitive to venlafaxine. It is contraindicated in those taking monoamine oxidase inhibitors (MAOIs). Do not use EFFEXOR XR in combination with an MAOI or within at least 14 days of discontinuing treatment with an MAOI because of the potential for serious adverse reactions. Based on the half-life of EFFEXOR XR, allow at least 7 days after stopping EFFEXOR XR before starting an MAOI.2



ADVERSE EVENTS

What are the principal adverse events seen with EFFEXOR XR?

The most common adverse events reported in EFFEXOR XR placebo-controlled trials (incidence >5% and >2x that of placebo) were nausea, dizziness, somnolence, abnormal ejaculation, sweating, dry mouth, nervousness, anorexia, abnormal dreams, and tremor.

Can they be minimized or avoided?

For some patients the 37.5-mg capsule is an initial dosing option to allow new patients to adjust to the medication before increasing to 75 mg/day.2

How can I help patients cope with side effects?

Counsel patients that certain adverse events, such as dizziness and nausea, usually diminish within the first 2 weeks.2

What is the incidence of sexual dysfunction with EFFEXOR XR?

Abnormal ejaculation was reported in 16% of men and 1% of women.2Impotence occurred in 4% of men.2

How often do significant blood-pressure increases occur?

Three percent of EFFEXOR XR patients treated with doses of 75 to 375 mg/day had sustained elevations in blood pressure. Fewer than 1% discontinued treatment because of it (versus 0.4% with placebo). Experience with immediate-release venlafaxine showed that sustained hypertension was dose related, increasing from 3% to 7% at doses of 100 mg/day to 300 mg/day, to 13% at doses above 300 mg/day.1 The incidence of sustained increases in blood pressure at doses greater than 300 mg/day has not been fully evaluated.2

Are drug-drug interactions a problem with EFFEXOR XR?

Venlafaxine has only a minimal effect on the cytochrome P450 hepatic enzyme system - the enzyme system that promotes the oxidative metabolism of numerous drugs.* Among the CYP450 isoenzymes, venlafaxine is unlikely to inhibit CYP3A4, as shown by in vivo effects on the pharmacokinetics of Seldane® (terfenadine). Tegretol® (carbamazepine), or XANAX® (alprazolam) C-IV, substrates for this isoenzyme.1

Other in vivo studies confirm that venlafaxine is also relatively weak inhibitor of CYP2D6 and has little or no inhibitory potential for CYP3A4, CYP1A2, and CYP2C19.10-12

What should patients do if they miss a dose of EFFEXOR XR?

Patients should take EFFEXOR XR at about the same time every day. However, if they miss a dose by more than several hours, they should skip the missed dose and wait to take the next dose as scheduled.

Does EFFEXOR XR have a discontinuation syndrome after abrupt termination of therapy, like the tricyclics and SSRIs?

Adverse events have followed the discontinuation of EFFEXOR XR,2like those seen with the tricyclics9 and SSRIs.13 The most common events after discontinuation of EFFEXOR XR (at an incidence >3% and >2x that of placebo) were dizziness, dry mouth, insomnia, nausea, nervousness, and sweating.2 It has been suggested that these phenomena may be attributed to serotonergic mechanisms in certain patients.14

Therefore, when discontinuing EFFEXOR XR after more than 1 week of therapy, taper the dose to minimize the risk of these symptoms. Patients discontinuing EFFEXOR XR after 6 weeks or more should have their dose tapered gradually over a 2-week period. In clinical trials, the dose was reduced by 75 mg at 1-week intervals. Individual patients may require different schedules for tapering.2

* Potential exists for a drug interaction between EFFEXOR XR and drugs which inhibit CYP2D6.

  Seldane is a registered trademark of Hoechst Marion Roussel; Tegretol is registered trademark of CibaGeneva Pharmaceuticals; Xanax is a registered trademark of Pharmacia & Upjohn.




Important Treatment Considerations


EFFEXOR XR is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). EFFEXOR XR should not be used in combination with an MAOI or within at least 14 days of discontinuing treatment with an MAOI because of potential for serious adverse reactions. Based on the half-life of EFFEXOR XR, at least 7 days should be allowed after stopping EFFEXOR XR before starting an MAOI.

Treatment with venlafaxine is associated with sustained increases in blood pressure (BP) in some patients. Three percent of EFFEXOR XR patients treated with doses of 75 to 375 mg/day had sustained BP elevations. The incidence of sustained increases in blood pressure at doses greater than 300 mg/day has not been fully evaluated. Less than 1% discontinued treatment because of elevated BP (versus 0.4% with placebo). Experience with immediate-release venlafaxine showed that sustained hypertension was dose related, increasing from 3% to 7% at doses of 100 mg/day to 300 mg/day, to 13% at doses above 300 mg/day.1 Regular BP monitoring is recommended.

Low potential exists for interaction in patients taking lithium, diazepam, or cimetidine.2 In combination with cimetidine, EFFEXOR XR should be used with caution in patients with preexisting hypertension, or in elderly patients, or in patients with hepatic dysfunction, as the interaction between the two drugs in these patients is not known and could be more pronounced.

Venlafaxine at a steady state increased the AUC of a single dose of haloperidol by 70%. The mechanism explaining this finding is unknown.

The most common adverse events reported in EFFEXOR XR placebo-controlled trials (incidence >5% and >2x that of placebo) were nausea, dizziness, somnolence, abnormal ejaculation, sweating, dry mouth, nervousness, anorexia, abnormal dreams, and tremor.

As with any psychotropic drug, EFFEXOR XR may impair judgment, thinking, or motor skills; patients should be advised to exercise caution until they have adapted to therapy.


REFERENCES



Data on file, Wyeth, Philadelphia, Pa.
EFFEXOR ® (venlafaxine HCI) and EFFEXOR ® XR (venlafaxine HCI) Prescribing Information, Wyeth, Philadelphia, Pa.
Kalus O, Asnis GM, van Praag HM. The role of serotonin in depression. Psychiatric Annals. 1989;19:348-353.
Scott MA, Shelton PS, Gattis W. Therapeutic options for treating major depression, and the role of venlafaxine. Pharmacotherapy. 1996;16:352-365.
Muth EA, Haskins JT, Moyer JA, et al. Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol. 1986;35:4493-4497.
Katz MM, Maas JW, Frazer A, et al. Drug-induced actions on brain neurotransmitter systems and changes in the behaviors and emotions of depressed patients. Neuropsychopharmacology. 1994;11:89-100.
Manufacturers' Prescribing Information for sertraline hydrochloride, paroxetine hydrochloride, and fluoxetine hydrochloride. Physicians' Desk Reference ®. 51st ed. Montvale, NJ: Medical Economics Co; 1997:935-940, 2051-2053, 2681-2686.
Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is catalyzed by CYP2D6. Br J Clin Pharmacol. 1996;41:149-156.
Garner EM, Kelly MW, Thompson DF. Tricyclic antidepressant withdrawal syndrome. Ann Pharmacother. 1993;27:1068-1072.
Krishnan KRR, Steffens DC, Doraiswamy PM. Psychotropic drug interactions. Primary Psychiatry. 1996;3:21-45.
Ereshefsky L. Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol. 1996;16(suppl 2):37S-53S.
Shader RI, von Moltke LL, Schmider J, et al. The clinician and drug interactions - an update. J Clin Psychopharmacol. 1996;16:197-201.
Price JS, Waller PC, Wood SM, et al. A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal. Br J Clin Pharmacol. 1996;42:757-763.
Khan A. Letter. Psychiatric Annals. 1997;27:259.