DrugBuyers.Com: Effexor

Venlafaxine hydrochloride is a structurally novel antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [(dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87.

Venlafaxine hydrochloride 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 octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

Effexor: Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate.

Effexor XR: Effexor XR is formulated as an extended release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, and titanium dioxide.

INDICATIONS

Venlafaxine hydrochloride is indicated for the treatment of depression. Venlafaxine HCl extended-release is indicated for depression and Generalized Anxiety Disorder.

WARNINGS

Potential for Interaction with Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine HCl, or who have recently had venlafaxine HCl therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, it is recommended that venlafaxine HCl not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine HCl, at least 7 days should be allowed after stopping venlafaxine HCl before starting an MAOI.

Sustained Hypertension

Immediate Release Tablets: Venlafaxine treatment is associated with sustained increases in blood pressure. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ³ 90 mm Hg and ³ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine.

An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (
Nevertheless, sustained increases of this magnitude could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine 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.

Extended Release Tablets: Venlafaxine is associated with sustained increases in blood pressure in some patients. Among patients treated with 75-375 mg per day of venlafaxine HCl (extended release) in premarketing studies, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) ³90 mm Hg and ³10 mm Hg above baseline for 3 consecutive on-therapy visits]. Experience with the immediate-release venlafaxine showed that sustained hypertension was dose-related, increasing from 3-7% at 100-300 mg per day to 13% at doses above 300 mg per day. An insufficient number of patients received mean doses of venlafaxine HCl (extended release) > 300 mg/day to fully evaluate the incidence of sustained blood pressure at these higher doses.

In placebo-controlled premarketing depression studies with venlafaxine HCl (extended release) 75-225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for extended release venlafaxine HCl-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients.

In premarketing depression studies, 0.7% (5/705) of the extended release venlafaxine HCl-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12-16 mm Hg, SDBP).

Sustained increases of SDBP could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine HCl (extended release) 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.

PRECAUTIONS

General

Insomnia and Nervousness

Immediate Release Tablets: Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short-term, double-blind, placebo-controlled depression studies.

Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the phase 2-3 depression studies.

Extended Release Capsules: Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine hydrochloride extended release capsules than with placebo in a pooled analysis of short-term depression studies.

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with venlafaxine HCl (extended release) in Phase 3 studies.

In Phase 3 GAD trials, insomnia and nervousness led to drug discontinuation in 5% and 3%, respectively, of the patients treated with venlafaxine HCl extended-release.

Changes in Appetite and Weight

Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (11% tablets/ 8% extended-release) than placebo treated patients (2% tablets/ 4% extended-release) in the pool of short-term, double-blind, placebo-controlled depression studies. A dose-dependent weight loss was often noted in patients treated with venlafaxine for several weeks. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of body weight occurred in 6% (7% extended-release) of patients treated with venlafaxine compared with 1% (2% extended-release) of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine tablets was uncommon (0.1% of venlafaxine-treated patients in the phase 2-3 depression trials). Discontinuation rates for anorexia and weight loss associated with venlafaxine HCl (extended release) were low (1.0% and 0.1%, respectively, of extended release venlafaxine HCl-treated patients in Phase 3 studies).

In the pool of short-term GAD studies, treatment-emergent anorexia was reported in 13% and 2% of patients receiving venlafaxine HCl extended-release and placebo, respectively. A loss of 7% or more of body weight occurred in 3% of the venlafaxine HCl extended-release-treated and 0% of the placebo-treated patients in these trials. Discontinuation rates for anorexia and weight loss were low (1.7% and 0.2% respectively, of venlafaxine HCl extended-release-treated patients).

Activation of Mania/Hypomania

During premarketing depression studies, mania or hypomania occurred in 0.3% of extended-release venlafaxine HCl-treated patients compared with 0.0% of placebo patients. In premarketing GAD studies, 0.0% of venlafaxine HCl extended-release patients and 0.5% of placebo-treated patients experienced mania or hypomania. In all premarketing depression trials with venlafaxine HCl, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed antidepressants. As with all antidepressants, venlafaxine HCl extended-release should be used cautiously in patients with a history of mania.

Seizures

During premarketing experience, no seizures occurred among 705 extended-release venlafaxine HCl-treated patients in the depression studies or among 476 venlafaxine HCl extended-release-treated patients in GAD studies. In all premarketing depression trials with venlafaxine HCl, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Venlafaxine HCl, like other antidepressants, should be used cautionsly in patients with a history of seizures and should be discontinued in any patient who develops seizures.

Suicide

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for venlafaxine HCl should be written for the smallest quantity of tablets or capsules consistent with good patient management in order to reduce the risk of overdose. The same precautions observed when treating patients with depression should be observed when treating patients with GAD.

Use in Patients with Concomitant Illness

Clinical experience with venlafaxine HCl in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine HCl to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

In patients with renal impairment (GFR=10-70 ml/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Venlafaxine hydrochloride, like all antidepressants, should be used with caution in such patients.

Venlafaxine HCl has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing.

Immediate-Release Tablets

Evaluation of the electrocardiograms for 769 patients who received venlafaxine HCl in 4 to 6 week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in venlafaxine HCl-treated patients was increased relative to baseline by about 4 beats per minute.

Extended-Release Capsules

The electrocardiograms for 357 patients who received venlafaxine HCl extended-release and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in depression and the electrocardiograms for 311 patients who received venlafaxine HCl extended-release and 153 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD were analyzed. The mean change from baseline in corrected QT interval (QT) for extended-release venlafaxine HCl-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine HCl extended-release and decrease of 1.9 msec for placebo). The clinical significance of these changes is unknown. The mean change from baseline in corrected QT interval (QTc) for venlafaxine HCl extended-release-treated patients in the GAD studies did not differ significantly from that with placebo.

In these same trials, the mean change from baseline in heart rate for extended release venlafaxine HCl-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine HCl (extended release) and 1 beat per minute for placebo). The mean change from baseline in heart rate for venlafaxine HCl extended-release-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minut for venlafaxine HCl extended-release and no change for placebo.) The clinical significance of these changes is unknown.

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe venlafaxine HCl:

Interference with Cognitive and Motor Performance: Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine HCl therapy does not adversely affect their ability to engage in such activities.

Concomitant Modification: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.

Alcohol: Although venlafaxine HCl has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine HCl.

Allergic Reactions: Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.

Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant.

Laboratory Tests

There are no specific laboratory tests recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.

Mutagenicity: Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-313 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose.

Impairment of Fertility: Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis.

Pregnancy, Teratogenic Effects, Pregnancy Category C

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

The effect of venlafaxine HCl on labor and delivery in humans is unknown.

Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from venlafaxine HCl extended-release, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Approximately 4% of extended-release venlafaxine HCl-treated patients in placebo-controlled premarketing depression and GAD trials were 65 years of age or over. Of 2897 immediate use venlafaxine HCl-treated patients in premarketing phase depression studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly.